Buprenorphine transdermal delivery system

ABSTRACT

A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing self-adhesive layer structure having (A) a buprenorphine-impermeable backing layer, and (B) a buprenorphine-containing pressure-sensitive adhesive layer on the backing layer. The buprenorphine-containing adhesive layer comprises (a) at least one polymer-based pressure-sensitive adhesive, (b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, (c) a viscosity-increasing substance in an amount of about 0.1% to about 8% of the buprenorphine-containing pressure-sensitive adhesive layer, and (d) a carboxylic acid selected from oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof. The amount of the carboxylic acid is sufficient so that the analgesically effective amount of buprenorphine is solubilized in the carboxylic acid to form a mixture including the viscosity-increasing substance. This mixture forms dispersed deposits in the pressure-sensitive adhesive. The buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a transdermal therapeutic system (TTS)for the transdermal administration of buprenorphine, and processes ofmanufacture, uses thereof, and corresponding methods of treatmenttherewith.

BACKGROUND OF THE INVENTION

The active ingredient buprenorphine(5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol)is a partially synthetic opiate with high potency. Cancer patients maybe treated with daily doses of around 1 mg. Despite its rather highmolecular weight of 467.64 daltons, it is currently used for transdermaladministration. The commercial TTS product Norspan®, also known asBuTrans®, delivers buprenorphine to the skin sufficiently to treatpatients in pain for a time period of 7 days (about 168 hours) andallows therefore a use of the TTS over a time period of 7 days andallows in a fixed dosing regimen a once-weekly TTS exchange. This isspecifically beneficial in terms of convenience and patient compliance.Thus the overall efficacy of the pain medicament is enhanced. However,the long administration periods may cause problems with skin irritation,which in combination with the considerable size (i.e., area of release)of the TTS may be problematic. Also, the large amount of excess drug inthe TTS necessary to sustain enough driving force for sustaining theappropriate drug delivery over the long period of time is costly and hasthe potential to be subject to illicit use.

It is therefore desirable to reduce the overall size (i.e., area ofrelease) of the TTS as well as the total amount of buprenorphine in theTTS before administration and also the amount remaining in the TTS afterproper use, the residual amount. Thereby, the amount of drug availablefor illicit use (before and after proper use), and the amount to bewasted after proper use are both reduced. US Patent Application No.2010/0119585 describes a certain TTS size and amount of drug reductionin comparison with the commercial TTS product Transtec® approved for anup-to-4 days administration regimen. Thus, the TTS needs to be replacedafter 4 days at the latest. It is recommended to change Transtec® twicea week always on the same days at specific times, e.g. Monday morningsand Thursday evenings.

For convenience reasons it is, however, desirable to maintain the onceweekly exchange mode (7 day dosing regimen) as, e.g., provided by thecommercial product Norspan® instead of the every three to four daysexchange mode as provided by, e.g., Transtec®.

The maintenance of sufficient release rates during a seven-dayadministration period is in particular challenging since the system isparticularly sensitive to variability in the drug release. The tolerancefor higher drug delivery at the beginning of the dosing period (alsoknow as “drug burst”) is very limited since the loss of drug at thebeginning will lead to a loss of driving force later in the dosingperiod, in particular after three to four days of delivery.

A drug burst at the beginning and the variability of such systems thusneed to be sufficiently controlled.

All references and publications cited herein are hereby incorporated byreference in their enteritis for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

A microreservoir system including deposits of buprenorphine and acarboxylic acid dispersed in a hydrophobic pressure sensitive adhesivelayer provides high overall release rates during a seven-dayadministration period allowing a reduction of size and drug content incomparison to the commercial product Norspan®. The manufacturing ofseveral batches, however, shows a high variability in the performance.These systems provide high performance but are biphasic due to thedispersed deposits (1. phase) in the adhesive (2. phase). Withoutwishing to be bound to any theory it is believed that the size and sizedistribution of the deposits influences the drug delivery. Largedeposits release the drug too fast and provide for an undesired burst inthe beginning of the dosing period and a failure of the system afterthree to four days. There is thus a need to sufficiently control thesize and size distribution of the deposits.

It is an object of certain embodiments of the present invention toprovide a transdermal therapeutic system for the transdermaladministration of buprenorphine (e.g., buprenorphine base), whichrequires a relatively small amount of buprenorphine (e.g., buprenorphinebase) contained therein and providing a sufficiently reproduciblerelease of buprenorphine (e.g., buprenorphine base), in particularproviding a reproducible release of buprenorphine (e.g., buprenorphinebase) suitable for providing pain relief for about 168 hours(corresponding to 7 days or one week).

It is an object of certain embodiments of the present invention toprovide a transdermal therapeutic system for the transdermaladministration of buprenorphine (e.g., buprenorphine base) whichrequires a relatively small area of release and providing a sufficientlyreproducible release of buprenorphine (e.g., buprenorphine base), inparticular providing a reproducible release of buprenorphine (e.g.,buprenorphine base) suitable for providing pain relief for about 168hours (corresponding to 7 days or one week).

It is an object of certain embodiments of the present invention toprovide reliable manufacturing processes for the above systems.

These objects and others are accomplished by the present invention,which according to one aspect relates to a transdermal therapeuticsystem for the transdermal administration of buprenorphine (e.g.,buprenorphine base), comprising a buprenorphine (e.g., buprenorphinebase) containing self-adhesive layer structure comprising

-   -   A) a buprenorphine (e.g., buprenorphine base) impermeable        backing layer, and    -   B) a buprenorphine (e.g., buprenorphine base) containing        pressure-sensitive adhesive layer on said        buprenorphine-impermeable backing layer, the adhesive layer        comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) a viscosity-increasing substance in an amount of about            0.1% to about 8% of said buprenorphine-containing            pressure-sensitive adhesive layer, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine (e.g.            buprenorphine base) is solubilized therein to form a mixture            including said viscosity-increasing substance, and wherein            the carboxylic acid-, buprenorphine- and            viscosity-increasing substance-containing mixture forms            dispersed deposits in said pressure-sensitive adhesive, and            wherein preferably said buprenorphine-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one specific aspect the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphine,comprising a buprenorphine-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) soluble polyvinylpyrrolidone, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the carboxylic acid-,            buprenorphine- and polyvinylpyrrolidone-containing mixture            forms dispersed deposits in the said pressure-sensitive            adhesive, and            wherein preferably said buprenorphine-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one specific aspect the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphinebase, comprising a buprenorphine base-containing self-adhesive layerstructure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,        -   c) soluble polyvinylpyrrolidone in an amount of about 1% to            about 4% of the buprenorphine base-containing            pressure-sensitive adhesive layer, wherein the            polyvinylpyrrolidone has a K-Value of at least about 80, and        -   d) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the levulinic acid-,            buprenorphine base- and polyvinylpyrrolidone-containing            mixture forms dispersed deposits in the said            pressure-sensitive adhesive, and            wherein preferably said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to further aspects the invention relates to a method oftreating pain in a patient by applying a transdermal therapeutic systemin accordance with the invention to the skin of a patient, in particularto a method of treating pain in a patient by applying a transdermaltherapeutic system in accordance with the invention to the skin of saidpatient for more than about 96 hours (or for more than 4 days), or forabout 120 hours (or for 5 days), or for about 144 hours (or for 6 days)or for about 168 hours (or for 7 days or for one week).

According to one specific aspect, the invention relates to a method oftreating pain in a patient by applying to the skin of said patient forabout 168 hours (or for 7 days or for one week) a transdermaltherapeutic system, comprising a buprenorphine (e.g., buprenorphinebase) containing self-adhesive layer structure comprising

-   -   A) a buprenorphine (e.g., buprenorphine base) impermeable        backing layer, and    -   B) a buprenorphine (e.g., buprenorphine base) containing        pressure-sensitive adhesive layer on said        buprenorphine-impermeable backing layer, the adhesive layer        comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) a viscosity-increasing substance in an amount of about            0.1% to about 8% of said buprenorphine-containing            pressure-sensitive adhesive layer, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine (e.g.            buprenorphine base) is solubilized therein to form a mixture            including said viscosity-increasing substance, and wherein            the carboxylic acid-, buprenorphine- and            viscosity-increasing substance-containing mixture forms            dispersed deposits in said pressure-sensitive adhesive, and            wherein preferably said buprenorphine-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one specific aspect, the invention relates to a method oftreating pain in a patient by applying for about 168 hours on the skinof a patient a transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising a buprenorphine-containingself-adhesive layer structure comprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) soluble polyvinylpyrrolidone, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the carboxylic acid-,            buprenorphine- and polyvinylpyrrolidone-containing mixture            forms dispersed deposits in the said pressure-sensitive            adhesive, and            wherein preferably said buprenorphine-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a method of treatingpain in a patient by applying to the skin of said patient for about 168hours a transdermal therapeutic system, comprising a buprenorphinebase-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,        -   c) soluble polyvinylpyrrolidone in an amount of about 1% to            about 4% of the buprenorphine base-containing            pressure-sensitive adhesive layer, wherein the            polyvinylpyrrolidone has a K-Value of at least about 80, and        -   d) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the levulinic acid-,            buprenorphine base- and polyvinylpyrrolidone-containing            mixture forms dispersed deposits in the said            pressure-sensitive adhesive, and            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a set of two to fivedifferent transdermal therapeutic systems for the transdermaladministration of buprenorphine base selected from five differenttransdermal therapeutic systems, i.e., a first, a second, a third, aforth and a fifth transdermal therapeutic system, each of the fivedifferent transdermal therapeutic systems comprising abuprenorphine-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,        -   c) soluble polyvinylpyrrolidone in an amount of about 1% to            about 4% of the buprenorphine base-containing            pressure-sensitive adhesive layer, wherein the            polyvinylpyrrolidone has a K-Value of at least about 80, and        -   d) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the levulinic acid-,            buprenorphine base- and polyvinylpyrrolidone-containing            mixture forms dispersed deposits in the said            pressure-sensitive adhesive, and            wherein,            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1 cm²            to about 4.8 cm² and contains from about 1 mg to about 4 mg            buprenorphine base;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9.5 cm² and contains from about 3.5 mg to about 8            mg buprenorphine base; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 19 cm² and contains from about 6.5 mg to about 16            mg buprenorphine base; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 12            cm² to about 28.5 cm² and contains from about 11.5 mg to            about 24 mg buprenorphine base; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 38 cm² and contains from about 15 mg to about            32 mg buprenorphine base,            wherein the five different transdermal therapeutic systems            have increasing areas of release and amounts of            buprenorphine from the first to the fifth transdermal            therapeutic system for use in method of treating pain by            applying one of said transdermal therapeutic systems for            about 168 hours on the skin of a patient. The set of two to            five different transdermal therapeutic systems in accordance            with this paragraph can be expanded by one or more further            transdermal therapeutic system(s) which may provide smaller,            greater or intermediate areas of release and amounts of            buprenorphine compared with the five different transdermal            therapeutic systems described above, preferably the set of            two to five different transdermal therapeutic systems is            expanded by a further transdermal therapeutic system which            provides a size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 5 cm² to about 14 cm² and            contains an amount of said buprenorphine from about 5.5 mg            to about 13 mg buprenorphine base or an equimolar amount of            a pharmaceutically acceptable salt thereof, providing an            intermediate transdermal therapeutic system between the            second and the third transdermal therapeutic system.            Alternatively, one of the transdermal therapeutic systems of            the set of two to five different transdermal therapeutic            systems described above can be replaced by such a further            transdermal therapeutic system.

According to one aspect, the invention relates to a set of transdermaltherapeutic systems including at least two transdermal therapeuticsystems selected from the first, second, third, fourth and fifthtransdermal therapeutic systems as described in the previous paragraphs.According to one specific aspect, the at least two transdermaltherapeutic systems can be selected from the first, second, third,fourth and fifth transdermal therapeutic system as described in theprevious paragraphs, and the further transdermal therapeutic systemwhich provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 5 cm² to about 14 cm² and contains an amount of saidbuprenorphine from about 5.5 mg to about 13 mg buprenorphine base.

According to one aspect, the invention relates to a method of treatingpain in a patient by selecting for said patient the appropriatetransdermal therapeutic system from the first, second, third, fourth andfifth transdermal therapeutic system as described in the previous twoparagraphs, and subsequently applying said selected transdermaltherapeutic system on the skin of said patient for about 168 hours.According to one specific aspect, the invention relates to a method oftreating pain in a patient by selecting for said patient the appropriatetransdermal therapeutic system from the first, second, third, fourth andfifth, and the further transdermal therapeutic system as described inthe previous two paragraphs, and subsequently applying said selectedtransdermal therapeutic system on the skin of said patient for about 168hours.

According to one aspect, the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphine,wherein buprenorphine is present in the form of buprenorphine base andproviding a non-cumulative release of buprenorphine base as measured ina Franz diffusion cell with dermatomed human skin of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168, andcomprising a buprenorphine base-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base,        -   c) a viscosity-increasing substance in an amount of about            0.1% to about 8% of said buprenorphine-containing            pressure-sensitive adhesive layer, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture including said            viscositiy-increasing substance, and wherein the carboxylic            acid-, buprenorphine base- and viscosity-increasing            substance-containing mixture forms dispersed deposits in the            said pressure-sensitive adhesive, and            wherein preferably said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer,            in particular for use in a method of treating pain by            applying the transdermal therapeutic system for about 168            hours on the skin of a patient.

The release characteristic can also be described in terms of a meannon-cumulative skin permeation rate of

0.25 μg/cm²-hr to 1.25 μg/cm²-hr in the first 8 hours,1.25 μg/cm²-hr to 5.0 μg/cm²-hr from hour 8 to hour 24,2.5 μg/cm²-hr to 10 μg/cm-hr² from hour 24 to hour 32,1.25 μg/cm²-hr to 5.0 μg/cm²-hr from hour 32 to hour 48,1.6 μg/cm²-hr to 6.25 μg/cm²-hr from hour 48 to hour 72,1.3 μg/cm²-hr to 4.2 μg/cm²-hr from hour 72 to hour 144, and1.25 μg/cm²-hr to 4.2 μg/cm²-hr from hour 144 to hour 168.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine, wherein buprenorphine is present in theform of buprenorphine base and providing a non-cumulative release ofbuprenorphine base as measured in a Franz diffusion cell with dermatomedhuman skin of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168, andcomprising a buprenorphine base-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base,        -   c) soluble polyvinylpyrrolidone, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the carboxylic acid-,            buprenorphine- and polyvinylpyrrolidone-containing mixture            forms dispersed deposits in the said pressure-sensitive            adhesive, and            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

The release charactersic can also be described in terms of a meannon-cumulative skin permeation rate of

0.25 μg/cm²-hr to 1.25 μg/cm²-hr in the first 8 hours,1.25 μg/cm²-hr to 5.0 μg/cm²-hr from hour 8 to hour 24,2.5 μg/cm²-hr to 10 μg/cm-hr² from hour 24 to hour 32,1.25 μg/cm²-hr to 5.0 μg/cm²-hr from hour 32 to hour 48,1.6 μg/cm²-hr to 6.25 μg/cm²-hr from hour 48 to hour 72,1.3 μg/cm²-hr to 4.2 μg/cm²-hr from hour 72 to hour 144, and1.25 μg/cm²-hr to 4.2 μg/cm²-hr from hour 144 to hour 168.

According to one specific aspect the invention relates to a method ofmanufacture of a transdermal therapeutic system for the transdermaladministration of buprenorphine in accordance with the invention,comprising the steps of

-   -   1. providing a buprenorphine-containing adhesive mixture        comprising        -   a) buprenorphine base or a pharmaceutically acceptable salt            thereof        -   b) a carboxylic acid,        -   c) a viscosity-increasing substance,        -   d) a polymer-based pressure-sensitive adhesive, and        -   e) solvent    -   2. storing said mixture between 0 hours and 6 days    -   3. homogenizing said buprenorphine-containing adhesive mixture        at a homogenizing at e.g. a speed of at least 1000 rpm;    -   4. storing said homogenized mixture between 0 hours and 6 days    -   5. coating said buprenorphine-containing adhesive mixture on a        film using a roller coater in an amount to provide the desired        coating dry weight,    -   6. drying said coated buprenorphine-containing adhesive mixture        to provide a buprenorphine-containing adhesive layer with the        desired coating dry weight,    -   7. optionally laminating said buprenorphine-containing adhesive        layer to a backing layer to provide an buprenorphine-containing        self-adhesive layer structure,    -   8. optionally punching the individual systems from the        buprenorphine-containing self-adhesive layer structure with the        desired area of release, and    -   9. optionally adhering to the individual systems an active        agent-free self-adhesive layer structure comprising also a        backing layer and an active agent-free pressure-sensitive        adhesive layer and which is larger than the individual systems        of buprenorphine-containing self-adhesive layer structure,        preferably wherein in step 1 buprenorphine is present in the        form of buprenorphine base, the carboxylic acid is levulinic        acid and the viscosity-increasing substance is        polyvinylpyrrolidone and all are dissolved in an appropriate        solvent (e.g. ethanol), and subsequently suspended in a        pressure-sensitive adhesive based on polysiloxane in an        appropriate solvent (e.g. heptanes) to provide the        buprenorphine-containing adhesive mixture or solution.

Useful solvents for dissolving buprenorphine, carboxylic acid and theviscosity-increasing substance are alcohols (e.g. ethanol), acetone andmethyl ethyl ketone, ethanol is preferred. The polymer-basedpressure-sensitive adhesive may be dissolved in heptanes, hexanes,toluene, or ethylacetate, preferably in heptane. The solvent forbuprenorphine has preferably only limited or no capability of dissolvingthe polymer-based pressure-sensitive adhesive and the solvent for thepolymer-based pressure-sensitive adhesive has preferably only limited orno capability of dissolving buprenorphine.

According to one aspect, the invention relates to the use ofpolyvinylpyrrolidone in the manufacture of a transdermal therapeuticsystem for the transdermal administration of buprenorphine which systemincludes deposits of a mixture including buprenorphine base and acarboxylic acid dispersed in a pressure-sensitive adhesive based onpolysiloxane to control the size of the deposits during the manufacture.

Within the meaning of this invention, the term “transdermal therapeuticsystem” (or TTS) refers to the entire individual unit that is applied tothe skin of a patient, and which comprises the buprenorphine-containingself-adhesive layer structure and optionally an additional largeractive-free self-adhesive layer structure on top of thebuprenorphine-containing self-adhesive layer structure, which TTSprovides the percutaneous delivery of the active buprenorphine to thepatient. During storage, such a TTS is normally located on aredetachable protective layer from which it is removed immediatelybefore application to the surface of the patient's skin. A TTS protectedthis way may be stored in a blister pack or a side sealed bag.

Within the meaning of this invention, the term “buprenorphine-containingself-adhesive layer structure” refers to the active agent-containingstructure providing the area of release of the active agent.

Within the meaning of this invention, “polymer-based pressure-sensitiveadhesive” refers to a pressure-sensitive adhesive containing from 75% to100% of said polymer based on the dry weight of the pressure-sensitiveadhesive, e.g., 75% to 100% of polysiloxane. According to certainembodiments the pressure-sensitive adhesive contains from 80% to 100%,or from 85% to 100%, or from 90% to 100%, or from 95% to 100% of thepolymer (e.g., polysiloxane) based on the dry weight of the pressuresensitive adhesive. A pressure-sensitive adhesive is in particular amaterial that adheres with finger pressure, is permanently tacky, exertsa strong holding force and should be removable from smooth surfacewithout leaving a residue. Examples of useful pressure-sensitiveadhesives based on polysiloxane which are commercially available includethe standard Bio-PSA series (7-4400, 7-4500 and 7-4600 series), theamine compatible (endcapped) Bio-PSA series (7-4100, 7-4200 and 7-4300series) and the Soft Skin Adhesives series (7-9800) manufactured by DowCorning. Preferred pressure-sensitive adhesives based on polysiloxaneare heptane-solvated pressure-sensitive adhesives including BIO-PSA7-4201, BIO-PSA 7-4301 and BIO-PSA 7-4501.

Within the meaning of this invention, the term “additional larger activeagent-free self-adhesive layer structure” refers to a self-adhesivelayer structure that is free of active agent and larger in area than theactive agent-containing structure and providing additional area adheringto the skin, but no area of release of the active agent, and enhancingthereby the overall adhesive properties of the TTS.

Within the meaning of this invention, the term “buprenorphine-containingpressure-sensitive adhesive layer” and “matrix layer” have the samemeaning and refer to the layer containing the active agent (thebuprenorphine) in a matrix-type structure of active in-adhesive. %amount of ingredients refers to the solid contents.

Within the meaning of this invention, the term “skin contact layer”refers to the part of the TTS which is in direct contact with the skinof the patient during administration and is located in/co-extensive withthe buprenorphine-containing self-adhesive layer structure. The sizes ofthe “skin contact layer” and the buprenorphine-containing self-adhesivelayer structure are co-extensive and correspond to the area of release.

Within the meaning of this invention, the term “deposit” as used inreference to “dispersed deposits” refers to distinguishable, e.g.,visually distinguishable, areas within the pressure-sensitive adhesive.Such deposits are e.g., droplets. Deposits that are visuallydistinguishable may be identified by use of a microscope.

Within the meaning of this invention, the term “viscosity-increasingsubstance” refers to a substance which when added to the mixture ofbuprenorphine and carboxylic acid increases the viscosity of themixture.

Within the meaning of this invention, the K-value refers to a valuecalculated from the relative viscosity of polyvinylpyrrolidone in wateraccording to the Ph.Eur. and USP monographs for “Povidone”.

Within the meaning of this invention the term “solublepolyvinylpyrrolidone” refers to polyvinylpyrrolidone which is solublewith more than 10% in at least ethanol, preferably also in water,diethylene glycol, methanol, n-propanol, 2-propanol, n-butanol,chloroform, methylene chloride, 2-pyrrolidone, macrogol 400, 1,2propylene glycol, 1,4 butanediol, glycerol, triethanolamine, propionicacid and acetic acid. Such soluble polyvinylpyrrolidone is supplied byBASF as Kollidon 12 PF, Kollidon 17 PF, Kollidon 25, Kollidon 30 andKollidon 90 F. Kollidon 90 F is used throughout the examples.

Within the meaning of this invention, the size of the deposits refers tothe diameter of the deposits as measured using a microscopic picture ofthe layers structure.

Within the meaning of this invention, the term “roll coater” refers to acoater which provides a coating whereby the fluid flow in a nip betweena pair of rotating rolls controls both the thickness and the uniformityof the coated film.

Within the meaning of this invention the “in-vitro dissolution” isdetermined using a rotating cylinder apparatus of the Ph Eur/USP using600 ml degassed 0.9% sodium chloride solution at 32° C. and rotated at50 rpm. At 0.5, 2, 8 (or 5) and 24 hours, 4 ml samples are removed andanalyzed by a reverse phase HPLC method using a mobile phase of 55:45%v/v acetonitrile:0.05 M potassium dihydrogen phosphate (adjusted to pH3.5) and UV detection at 220 nm.

Within the meaning of this invention, the parameter “mean cumulativeskin permeation rate” is provided in μg/cm²-hr and is calculated fromthe cumulative release as measured by in vitro experiments carried outwith the Franz diffusion cell over the total time period of release,e.g., 168 hours, in μg/cm² divided by the hours corresponding to saidtotal time period of release, e.g., 168 hours, taking into account a lagtime of 24 hours.

Within the meaning of this invention, the parameter “mean non-cumulativeskin permeation rate” is provided in μg/cm²-hr and is calculated fromthe non-cumulative release of a certain sample interval as measured in aFranz diffusion cell in μg/cm² divided by the hours of said sampleinterval.

Within the meaning of this invention, the parameter “cumulative release”is provided in μg/cm² and relates to the total amount released over thetotal time period of release, e.g., 168 hours, as measured in a Franzdiffusion cell. The value is a mean value of at least 3 experiments.

Within the meaning of this invention, the parameter “non-cumulativerelease” is provided in μg/cm² and relates to the amount released in asample interval at certain elapsed time within the total time period ofrelease, e.g., hour 16 of release corresponding to a sample interval of8 hours from hour 8 to hour 16 of release within 168 hours of total timeperiod of release, as measured in a Franz diffusion cell. The value is amean value of at least 3 experiments.

Within the meaning of this invention, the parameter “mean release rate”refers to the mean release rate in μg/hr over the period ofadministration (e.g., 7 days) by which the active agent permeatesthrough the human skin into the blood system and is based on the AUCobtained over said period of administration in a clinical study.

Within the meaning of this invention, the parameter “nominal meanrelease rate” refers to an assigned mean release rate determined bycomparison with the commercial reference product BuTrans® which isapplied for 7 days to the skin of the subjects and of which mean releaserates are publicly available from the package insert. The correspondingknown nominal mean release rate of the 25 cm² area of release BuTrans®reference TTS containing 20 mg buprenorphine is 20 μg/hr. The meanrelease rate is proportional to the size of the area of release of a TTSand may be used to distinguish TTS's by the dosage strength. TheBuTrans® TTS with half the size (i.e. 12.5 cm² area of release) andcontaining 10 mg of buprenorphine provides the known nominal meanrelease rate of 10 μg/hr. The BuTrans® TTS with a size of 6.25 cm² areaof release and containing 5 mg of buprenorphine provides the knownnominal mean release rate of 5 μg/hr. Accordingly, it can be assumedthat a corresponding TTS with a size of 50 cm² area of release andcontaining 40 mg of buprenorphine provides a nominal mean release rateof 40 μg/hr, and a corresponding TTS with a size of 37.5 cm² area ofrelease and containing 30 mg of buprenorphine provides a nominal meanrelease rate of 30 μg/hr, and a corresponding TTS with a size of 18.75cm² area of release and containing 15 mg of buprenorphine provides anominal mean release rate of 15 μg/hr. The nominal mean release ratesare assigned to the TTSs in accordance with the invention by comparingthe Franz diffusion cell skin permeation rates of the reference TTSBuTrans® with the Franz diffusion cell skin permeation rates of theTTS's in accordance with the invention.

Within the meaning of this invention, the meaning of “by applying to theskin of said patient for about 168 hours” corresponds to “by applying tothe skin of said patient for about 7 days or for one week” and refers toa once a week exchange mode or dosing regimen. Likewise, about 96 hourscorrespond to 4 days, about 120 hours correspond to 5 days and about 144hours correspond to 6 days. The term “applying to the skin of a patientfor a certain period of time” has the same meaning as “administrationfor a certain period of time”.

Within the meaning of this invention, the term “patient” refers to asubject who has presented a clinical manifestation of a particularsymptom or symptoms suggesting the need for treatment, who is treatedpreventatively or prophylactically for a condition, or who has beendiagnosed with a condition to be treated.

If not indicated otherwise “%” refers to weight-%.

Within the meaning of this invention, the term “active”, “active agent”,and the like, as well as the term “buprenorphine” refers tobuprenorphine base or a pharmaceutically acceptable salt thereof. Unlessotherwise indicated the amounts of buprenorphine in the TTS relate tothe amount of buprenorphine before administration of the TTS. Theamounts of buprenorphine in the TTS after administration are referred toas residual amounts.

Within the meaning of this invention, values and ranges specifying thesize of the area of release and the amount of buprenorphine contained inthe transdermal therapeutic system are mean values of at least 3measurements.

Within the meaning of this invention the term “pharmacokineticparameters” refers to parameters describing the blood plasma curve, e.g.Cmax, AUCt and AUCINF obtained in a clinical study, e.g. by single-doseadministration of the active agent TTS, e.g. the buprenorphine base TTSto healthy human subjects. The pharmacokinetic performance of the TTSsin accordance with the invention can be deduced from the performance ofthe buprenorphine-containing microreservoir systems disclosed in theinternational application PCT/IB2012/002973 (see e.g. pages 69 to 100 ofPCT/IB2012/002973). The pharmacokinetic parameters of the individualsubjects are summarized in PCT/IB2012/002973 using arithmetic andgeometric means, e.g. a mean Cmax, a mean AUCt and a mean AUCINF, andadditional statistics such as the respective standard deviations andstandard errors, the minimum value, the maximum value, and the middlevalue when the list of values is ranked (Median). In the context of thepresent invention, pharmacokinetic parameters, e.g. the mean Cmax, themean AUCt and the mean AUCINF refer to geometric mean values if notindicated otherwise. It cannot be precluded that the absolute meanvalues obtained for a certain TTS in a clinical study vary to a certainextend from study to study. To allow a comparison of absolute meanvalues between studies, a reference formulation, e.g. the commercialreference product BuTrans® or in the future any product based on theinvention, may be used as internal standard. A comparison of the AUC perarea of release, e.g. the mean AUCt per area of release of therespective reference product in the earlier and later study can be usedto obtain a correction factor to take into account differences fromstudy to study. In the clinical study described in PCT/IB2012/002973 thecommercial reference product BuTrans® provides an AUCt per area ofrelease of 1624.53 pg·hr/ml-cm². It was shown in the same study thatmicroreservoir systems including deposits of buprenorphine and acarboxylic acid dispersed in a hydrophobic pressure sensitive adhesivelayer provide a better performance in terms of the AUCt per area ofrelease compared with the commercial product BuTrans®, i.e., Examples 1and 2 of PCT/IB2012/002973 provide an AUCt per area of release of2690.49 pg·hr/ml-cm² and 2746.86 pg·hr/ml-cm², respectively. Themicroreservoir systems thus provide an about 1.7-fold better performancethan the commercial product BuTrans® in the same study.

Clinical studies according to the present invention refer to studiesperformed in full compliance with the International Conference forHarmonization of Clinical Trials (ICH) and all applicable local GoodClinical Practices (GCP) and regulations.

Within the meaning of this invention, the term “healthy human subject”refers to a male or female subject with a body weight ranging from 55 kgto 100 kg and a body mass index (BMI) ranging from 18 to 29 and normalphysiological parameters, such as blood pressure, etc. Healthy humansubjects for the purposes of the present invention are selectedaccording to inclusion and exclusion criteria which are based on and inaccordance with recommendations of the ICH.

Within the meaning of this invention, the term “subject population”refers to at least ten individual healthy human subjects.

Within the meaning of this invention, the term “geometric mean” refersto the mean of the log transformed data backtransformed to the originalscale.

Within the meaning of this invention, the term “arithmetic mean” refersto the sum of all values of observation divided by the total number ofobservations.

Within the meaning of this invention, the parameter “AUC” corresponds tothe area under the plasma concentration-time curve. The AUC value isproportional to the amount of active agent absorbed into the bloodcirculation in total and is hence a measure for the bioavailability.

Within the meaning of this invention, the parameter “AUCt” is providedin pg·hr/ml and relates to the area under the plasma concentration-timecurve from hour 0 to the last measurable plasma concentration and iscalculated by the linear trapezoidal method.

Within the meaning of this invention, the parameter “mean AUCt per areaof release” is provided in pg·hr/ml-cm² and is calculated from thegeometric mean AUCt as determined for a certain TTS in pg·hr/ml dividedby the area of release of said TTS.

Within the meaning of this invention, the parameter “AUCINF” is providedin pg·hr/ml and relates to the area under the plasma concentration-timecurve extrapolated to infinity and is calculated using the formula:

${AUCINF} = {{AUCt} + \begin{matrix}{CLast} \\{Lambdaz}\end{matrix}}$

where CLast is the last measurable plasma concentration and LambdaZ isthe apparent terminal phase rate constant.

Within the meaning of this invention, the parameter “Cmax” is providedin pg/ml and relates to the maximum observed blood plasma concentrationof the active agent.

Within the meaning of this invention, the parameter “tmax” is providedin hr and relates to the time point at which the Cmax value is reached.In other words, tmax is the time point of the maximum observed plasmaconcentration.

Within the meaning of this invention, the parameter “LambdaZ” isprovided in 1/hr and relates to the apparent terminal phase rateconstant, where LambdaZ is the magnitude of the slope of the linearregression of the log concentration versus time profile during theterminal phase.

Within the meaning of this invention, the parameter “t1/2Z” is providedin hr and relates to the apparent plasma terminal phase half-life and iscommonly determined as t1/2Z=(ln2)/LambdaZ.

Within the meaning of this invention, the term “mean plasmaconcentration” is provided in pg/ml and is a mean of the individualplasma concentrations of active agent, e.g. buprenorphine base, at eachpoint in time.

Within the meaning of this invention, the term “bioequivalent” isdefined to refer to a TTS that provides geometric mean values of Cmax,AUCt, and AUCINF for buprenorphine, wherein the 90% confidence intervalsestimated for the ratio test/reference fall within the range of 80.00%to 125.00%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a microscopic picture of the matrix layer of ComparativeExample 1.

FIG. 2A depicts a microscopic picture of the buprenorphinebase-containing adhesive mixture of Comparative Example 2.

FIG. 2B depicts a microscopic picture of the matrix layer of ComparativeExample 2.

FIG. 3A depicts a microscopic picture of the buprenorphinebase-containing adhesive mixture of Example 3.

FIG. 3B depicts a microscopic picture of the matrix layer of Example 3.

FIG. 4A depicts a microscopic picture of the buprenorphinebase-containing adhesive mixture of Example 4.

FIG. 4B depicts a microscopic picture of the matrix layer of Example 4.

FIG. 5 depicts the mean in-vitro-dissolution of Comparative Example 1.

FIG. 6 depicts the mean in-vitro-dissolution of Comparative Example 2.

FIG. 7 depicts the mean in-vitro-dissolution of Example 3.

FIG. 8 depicts the mean in-vitro-dissolution of Example 4.

FIG. 9 depicts the mean non-cumulative skin permeation rates forComparative Examples 1 and 2 and Norspan®.

FIG. 10 depicts the mean non-cumulative skin permeation rates forExamples 6, 7.1, 8 and BuTrans®.

FIG. 11 depicts the mean non-cumulative skin permeation rates forExamples 7.1, 7.2 and BuTrans®.

FIG. 12 depicts the mean non-cumulative skin permeation rates forExamples 7.2, 5.2 and BuTrans®.

FIG. 13 depicts the mean non-cumulative skin permeation rate of the ofthe transdermal therapeutic systems. The area of release of thetransdermal therapeutic system according to Example 5.2 is 14 cm² andthe area of release for BuTrans® is 25 cm². The amount of buprenorphinebase for Example 5.2 is 12.6 mg and the amount of buprenorphine base forBuTrans® is 20 mg.

DETAILED DESCRIPTION

A microreservoir system including deposits of buprenorphine and acarboxylic acid dispersed in a hydrophobic pressure-sensitive adhesivelayer provides high overall release rates during a seven-dayadministration period, thereby allowing a reduction of size and drugcontent of the TTS in comparison to the commercial product Norspan®.Such systems are described in the parallel patent applicationPCT/US2012/069242, corresponding to PCT/IB2012/002973, which is herebyincorporated by reference. In particular reference is made to Examples 1to 4 in PCT/US2012/069242, corresponding to PCT/IB2012/002973. Themanufacturing of several batches, however, shows a high variability inthe performance. These systems provide high performance but are biphasicdue to the dispersed deposits (1. phase) in the adhesive (2. phase).Without wishing to be bound to any theory, it is believed that the sizeand size distribution of the deposits influences the drug delivery.Large deposits release the drug too fast and provide for an undesiredburst in the beginning of the dosing period and a failure of the systemafter three to four days. There is thus a need to sufficiently controlthe size and size distribution of the deposits.

The production of a commercial transdermal product as disclosed hereinrequires a continuous coating and drying process to form thebuprenorphine-containing pressure sensitive adhesive layer. Such coatingis usually accomplished with a sufficiently sized roller coater andattached drying compartment. The buprenorphine-containing mixture to becoated is usually prepared batch wise, and is then stored for some timeuntil the coater is ready to coat the mixture. The time between thepreparation of the mixture and the coating of the mixture in a normalproduction routine can be almost zero, if after mixing/homogenizing themass will be transferred to the coating station and is coated directlyand may be as long as several days, e.g. four to six days, to store themixture during the time of a failure of the coater or a weekend or otherreasons for a coating process interruption. Thus the mixture must besufficiently stable. A microreservoir system as described hereinincluding two phases, namely the deposits and the adhesive surroundingthe deposits which may change over time due to the fusion of individualdeposits forming larger deposits. Thus the deposits must be hindered infusing during the stoning time between mixing and coating.

Additionally, the shearing force applied to the coating mixture duringcoating in a roller coater is different and higher than on a laboratoryscale coating technique like such as when using the Erichsen coater. Butfor commercial scale production, a roller coater is necessary to providethe necessary scale up and the necessary coating precision. However, theshear force in a roller coater causes additional fusion of the deposits.Thus the deposits must be hindered in fusing during the coating processusing a roller coater.

TTS Structure

According to a certain embodiment of the invention the transdermaltherapeutic system for the transdermal administration of buprenorphinecomprises a buprenorphine-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) a viscosity-increasing substance in an amount of about            0.1% to about 8% of said buprenorphine-containing            pressure-sensitive adhesive layer, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture including said            viscositiy-increasing substance, and wherein the carboxylic            acid-, buprenorphine- and viscosity-increasing            substance-containing mixture forms dispersed deposits in the            said pressure-sensitive adhesive, and            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is preferably the skin contact layer.

Without wishing to be bound to any theory it is believed that theviscosity-increasing substance increases the viscosity of the deposits(inner phase) within the adhesive solution (outer phase) during theproduction and within the adhesive matrix (outer phase) during thestorage of the dried buprenorphine-containing layer.

Useful viscosity-increasing substances may be selected from the groupconsisting of cellulose derivatives such as methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, and microcrystalline cellulose, high molecularmass polyacrylic acids and/or their salts and/or their derivatives suchas esters, polyvinylpyrrolidone, in particular solublepolyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate,tragacanth, xanthan gum, bentonite, carageenan and guar gum. A preferredviscosity-increasing substance is polyvinylpyrrolidone.

In certain embodiments of the invention the viscosity-increasingsubstance is present in an amount of about 0.1% to about 7%, or in anamount of about 0.5% to about 5%, preferably in an amount of about 1% toabout 4%, more preferably in an amount of about 2% to about 3% of thebuprenorphine-containing pressure-sensitive adhesive layer.

According to a certain independent embodiments of the invention whereinthe structure is concerned, the transdermal therapeutic system for thetransdermal administration of buprenorphine comprises abuprenorphine-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof,        -   c) soluble polyvinylpyrrolidone, and        -   d) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the carboxylic acid-,            buprenorphine- and polyvinylpyrrolidone-containing mixture            forms dispersed deposits in the said pressure-sensitive            adhesive, and            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.

Without wishing to be bound to any theory it is believed that thepolyvinylpyrrolidone having a K-Value of at least 5, at least 10, atleast 15, at least 20, at least 50, or a K-Value of at least 80 is inparticular beneficial in increasing the viscosity of the deposits (innerphase) within the adhesive solution (outer phase) during the productionand within the adhesive matrix (outer phase) during the storage of thedried buprenorphine-containing layer. The increase in viscosity sibeneficial because the deposits are thereby hindered in fusing duringthe storing time between mixing and coating.

In certain embodiments of the invention the transdermal therapeuticsystem for the transdermal administration of buprenorphine comprises abuprenorphine-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,        -   c) soluble polyvinylpyrrolidone in an amount of about 1% to            about 4% of the buprenorphine base-containing            pressure-sensitive adhesive layer, wherein the            polyvinylpyrrolidone has K-Value of at least about 80, and        -   d) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture including said            polyvinylpyrrolidone, and wherein the levulinic acid-,            buprenorphine base- and polyvinylpyrrolidone-containing            mixture forms dispersed deposits in the said            pressure-sensitive adhesive, and            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to a certain other embodiment of the invention alternativelythe buprenorphine-containing pressure-sensitive adhesive layer comprisesan additional skin contact layer.

According to certain embodiments of the invention, the TTS comprises inaddition to the buprenorphine-containing self-adhesive layer structureattached thereto a larger active agent-free self-adhesive layerstructure, e.g., a peripheral adhesive or overlying adhesive, forenhancing the adhesive properties of the overall transdermal therapeuticsystem. Said active agent-free self-adhesive layer structure comprisesalso a backing layer. In certain embodiments, this additional layer isbeige colored. The active agent-free pressure-sensitive adhesive layerof polymer-based pressure-sensitive adhesive is e.g., based onpolyacrylates or polysiloxanes. The area of said second activeagent-free self-adhesive layer structure adds to the overall size of theTTS but does not add to the area of release. The pressure-sensitiveadhesive in the active agent-containing and the active agent-freeself-adhesive layer structures may be the same or different. If theadhesive in the active agent-free self-adhesive layer is different fromthat of the buprenorphine-containing layer, then pressure-sensitiveadhesives selected from the group of polyacrylate-based orpolyisobutylene-based pressure-sensitive adhesives can be used, andpolyacrylate based pressure-sensitive adhesives are preferred, inparticular pressure-sensitive adhesives based on anacrylate-vinylacetate polymer, e.g., such as those available from Henkelunder the tradename Duro Tak®, e.g., Duro Tak® 387 2051. Suchpressure-sensitive adhesives are provided in an organic solution ofethyl acetate and heptane. Such pressure-sensitive adhesives provide a180° Peel at 20 minutes of at least about 20 N/25 mm, and at 24 minutesof at least about 25 N/25 cm, and at one week of at least about 30 N/25mm and a Loop tack of at least 15 N/25 mm², or of at least 20 N/25 mm²,or of at least 22 N/25 mm².

Active Agent

The TTS according to the invention comprises an analgesically effectiveamount of buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof. Pharmaceutically acceptablesalts may be selected from those known in the art, such as thehydrochloride, sulphate, phosphate, tartrate, maleinate, oxalate,acetate and lactate salts. According to a preferred embodiment of theinvention the active agent is included in the form of buprenorphinebase. The term buprenorphine base, however, does not excludeinteractions, including complexation between the buprenorphine base andother ingredients of the buprenorphine-containing layer e.g. levulinicacid.

An analgesically effective amount may vary from about 1 mg to about 50mg, in particular from about 2 mg to about 30 mg of buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt, or fromabout 2 mg to about 25 mg of buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof. According to certainembodiments, the TTS contains according to five different dosages fromabout 1 mg to about 4 mg, or from about 3.5 mg to about 8 mg, or fromabout 6.5 mg to about 16 mg, or from about 11.5 mg to about 24 mg, orfrom about 15 mg to about 32 mg of buprenorphine base or a an equimolaramount of a pharmaceutically acceptable salt thereof, or the TTScontains according to five different dosages from about 1 mg to about4.5 mg, or about 3 mg, or from about 4 mg to about 9 mg, or about 6 mg,or from about 8 mg to about 14 mg, or about 12 mg, or from about 15 mgto about 20 mg, or about 18 mg or from about 20 mg to about 28 mg, orabout 24 mg of buprenorphine base or a an equimolar amount of apharmaceutically acceptable salt thereof. Further dosages are providedby transdermal therapeutic systems containing smaller or greateramounts, e.g., from about 5.5 mg to about 13 mg of buprenorphine base oran equimolar amount of a pharmaceutically acceptable salt thereof.

Pressure-Sensitive Adhesive

The pressure-sensitive adhesives used for the present invention arepolymer-based pressure-sensitive adhesives. Such polymer-basedpressure-sensitive adhesives may e.g., be based on polysiloxanes orpolyisobutylenes. For the present invention polysiloxane-basedpressure-sensitive adhesives are preferred. Such polysiloxanes adhesivesneed, unlike other organic pressures-sensitive adhesives, no additiveslike antioxidants, stabilizers, plasticizers, catalysts or otherpotentially extractable ingredients. These pressure-sensitive adhesivesprovide for suitable tack for quick bonding to various skin types,including wet skin, suitable adhesive and cohesive qualities, longlasting adhesion to the skin of up to 7 days, a high degree offlexibility, a permeability to moisture, and compatibility to manyactives and film-substrates. It is possible to provide them withsufficient amine resistance and therefore enhanced stability in thepresence of amines. Such pressure-sensitive adhesives are based on aresin-in-polymer concept wherein, by condensation reaction of silanolend blocked polydimethylsiloxane with a silica resin, a polysiloxane isprepared which for amine stability the residual silanol functionality isadditionally capped with trimethylsiloxy groups. The dimethiconolcontent contributes to the viscous component of the visco-elasticbehavior, and impacts the wetting and the spreadability properties ofthe adhesive. The resin acts as a tackifying and reinforcing agent, andparticipates in the elastic component. The correct balance betweendimethiconol and resin provides for the correct adhesive properties.

The adhesive strength of the polysiloxanes may be sufficient for thedesired skin contact. In certain embodiments of the invention aplasticizer or a tackifying agent is incorporated into the formulationto improve the adhesive characteristics of the pressure-sensitiveadhesive layer. It may be advantageous in an individual case to improvethe tack by adding small amounts of tackifiers such as polyterpenes,rosin derivatives, or silicone oils. In preferred embodiments, thetackifying agent is a silicone oil (e.g., 360 Medical Fluid, availablefrom Dow Corning Corporation, Midland, Mich.).

The pressure-sensitive adhesives are supplied and used in solvents likeheptane, ethyl acetate or volatile silicone fluids. For the presentinvention heptane is preferred. The solids content is usually between 60and 80%.

The preferred pressure-sensitive adhesives based on polysiloxanes inaccordance with the invention are characterized by a solution viscosityat 25° C. and 60% solids content in heptane of more than about 150 mPas, or from about 200 mPa s to about 700 mPa s, in particular from about350 mPa s to about 600 mPa s, more preferred from about 480 mPa s toabout 550 mPa s, or most preferred of about 500 mPa s or alternativelyfrom about 400 mPa s to about 480 mPa s, or most preferred of about 450mPa s. Theses may also be characterized by a complex viscosity at 0.01rad/s at 30° C. of less than about 1×10⁹ Poise, or from about 1×10⁵ toabout 9×10⁸ Poise, or more preferred from about 1×10⁵ to about 1×10⁷Poise, or most preferred about 5×10⁶ Poise, or alternatively morepreferred from about 2×10⁷ to about 9×10⁸ Poise, or most preferred about1×10⁸ Poise.

Suitable pressure-sensitive adhesives based on polysiloxanes may beobtained from Dow Corning® BIO-PSA Standard Silicone Adhesives.Preferred are the BIO-PSA 7 4301 and BIO-PSA 7 4201 Silicone Adhesives.According to certain embodiments BIO-PSA 7 4301 is preferred andaccording to certain other embodiments BIO-PSA 7 4201 is preferred. Toavoid excessive cold flow, BIO-PSA 7 4201 is preferred. BIO-PSA 4201 hasa solution viscosity at 25° C. and about 60% solids content in heptaneof 450 mPa s and a complex viscosity at 0.01 rad/s at 30° C. of 1×10⁸Poise. BIO-PSA 4301 has a solution viscosity at 25° C. and about 60%solids content in heptane of 500 mPa s and a complex viscosity at 0.01rad/s at 30° C. of 5×10⁶ Poise.

The pressure-sensitive adhesive layer of the TTS of the invention mayfurther comprise in addition to the above mentioned ingredients a), b),c) and d), (i.e. the polymer-based pressure-sensitive adhesive, thebuprenorphine, the viscosity-increasing substance/thepolyvinylpyrrolidone and the carboxylic acid selected from the group ofoleic acid, linoleic acid, linolenic acid and levulinic acid asdescribed herein), other various excipients or additives, selected, forexample, from the group of solubilizers, fillers, tackifiers, substanceswhich influence the barrier properties of the stratum corneum in thesense of increasing the active agent permeability, pH regulators, andpreservatives.

Substances which influence the barrier properties of the stratum corneumin the sense of increasing the active agent permeability are known tothe skilled worker and the substance appropriate for the respectiveactive agents must—if necessary—be found by means of permeation studies.Some examples are polyhydric alcohols such as dipropylene glycol,propylene glycol, and polyethylene glycol; oils such as olive oil,squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether;fatty acid esters such as isopropyl myristate; urea and urea derivativessuch as allantoin; polar solvents such as dimethyldecylphosphoxide,methyloctylsulfoxide, dimethyllaurylamine, dodecylpyrrolidone,isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide,and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate;and higher molecular weight aliphatic surfactants such as lauryl sulfatesalts. Other agents include oleic and linoleic acids, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate,tocopheryl linoleate, propyl oleate, and isopropyl palmitate. The TTS ofthe invention may additionally comprise according to certain embodiments(in which the pressure-sensitive adhesive layer comprises a) thepolymer-based pressure-sensitive adhesive, b) the buprenorphine, c) theviscosity-increasing substance/the polyvinylpyrrolidone and d) levulinicacid or linolenic acid or mixtures of both as the carboxylic acid asdescribed herein) oleic and linoleic acids as substances influencing thebarrier properties of the stratum corneum in the sense of increasing theactive agent permeability.

Such substances as described in the previous paragraph may be includedin a TTS and may be present in an amount of about 1% to about 10% byweight. In a preferred embodiment of the present invention suchadditional substances are however not necessary. According to anembodiment of the invention the TTS does not comprise such additionalsubstances as mentioned in the previous paragraph.

In addition to the carboxylic acid selected from oleic acid, linoleicacid, linolenic acid, levulinic acid, the solubility of the drug can befurther altered by the optional addition of an agent that increases thesolubility of drug or inhibits drug crystallization in the transdermalcomposition, such as vinyl acetate/vinylpyrrolidone copolymer andcellulose derivatives.

Fillers such as silica gels, titanium dioxide and zinc oxide may be usedin conjunction with the polymer in order to influence certain physicalparameters, such as cohesion and bond strength, in the desired way.

Further one or more anti-oxidants can be added. The anti-oxidant may beselected from the group consisting of tocopherol, esters thereof, e.g.α-tocopherol acetate, ascorbyl palmitate, ascorbic acid,butylhydroxytoluene, butylhydroxyanisole or propyl gallate, preferablyascorbyl palmitate. The antioxidant may be conveniently present in anamount of from about 0.01 to about 0.5%, e.g. 0.05 to 0.30, e.g. 0.18%or 0.2% of the buprenorphine-containing pressure-sensitive adhesivelayer.

Buprenorphine-Containing Self-Adhesive Layer Structure

In accordance with the invention, the buprenorphine-containingself-adhesive layer structure comprises a buprenorphine-impermeablebacking layer, and a buprenorphine-containing pressure-sensitiveadhesive layer coated thereon. In a preferred embodiment, thebuprenorphine-containing self-adhesive layer structure consists of thesetwo elements.

The buprenorphine-containing pressure-sensitive adhesive layer may becoated at any dry weight, but is preferably coated at a dry weight ofmore than about 6 mg/cm² (about 60 g/m²), or of more than about 8 mg/cm²(about 80 g/m²), or ranging from about 6 mg/cm² (about 60 g/m²) to about14 mg/cm² (about 140 g/m²), or from about 8 mg/cm² (about 80 g/m²) toabout 14 mg/cm² (about 140 g/m²). Specifically, the dry weight is morethan about 10 mg/cm² (about 100 g/m²), or ranges from about 10 mg/cm²(about 100 g/m²) to about 13 mg/cm² (about 130 g/m²), or ranges fromabout 11.5 mg/cm² (about 115 g/m²) to about 12.5 mg/cm² (about 125g/m²), or is specifically about 12 mg/cm² (about 120 g/m²).

The dry buprenorphine-containing pressure-sensitive adhesive layerpreferably contains buprenorphine base, but may contain an equimolaramount of a pharmaceutically acceptable salt. According to theinvention, preferably more than 5%, or more than about 6%, or more thanabout 7%, or more than about 8%, or more than about 9%, or from about 6%to about 20%, or from about 7% to about 20%, or from about 8% to about20%, or from about 9% to about 20%, or from about 6% to about 15%, orfrom about 7% to about 15%, or from about 8 to about 15%, or from about9 to about 15% buprenorphine base or an equimolar amount of apharmaceutically acceptable salt based on the total dry weight of thedry buprenorphine-containing pressure-sensitive adhesive layer iscontained in the dry buprenorphine-containing pressure-sensitiveadhesive layer. In a specific embodiment, about 10% buprenorphine baseis contained in the dry buprenorphine-containing pressure-sensitiveadhesive layer.

Preferably, the TTS contains in the pressure-sensitive adhesive layermore than about 0.55 mg/cm², or more than about 0.6 mg/cm², or more thanabout 0.7 mg/cm², or more than about 0.8 mg/cm², or more than about 0.9mg/cm², or more than about 1 mg/cm², or more than about 1.1 mg/cm²,buprenorphine base, or from about 0.55 mg/cm² to about 2 mg/cm², or fromabout 0.6 mg/cm² to about 2 mg/cm², or from about 0.7 mg/cm² to about 2mg/cm², or from about 0.8 mg/cm² to about 2 mg/cm², or from about 0.9mg/cm² to about 2 mg/cm², or from about 1 mg/cm² to about 2 mg/cm², orfrom about 1.1 mg/cm² to about 2 mg/cm² buprenorphine base or containsabout 1.2 mg/cm² buprenorphine base. The TTS may also contain equimolaramounts of pharmaceutically acceptable salts.

In order to provide the desired delivery rate of buprenorphine, acarboxylic acid is present. The carboxylic acid may be selected from thegroup consisting of C₃ to C₂₄ carboxylic acids including oleic acid,linoleic acid, linolenic acid, levulinic acid and mixtures thereof,wherein levulinic acid is preferred. Alternatively or in addition, asubstance selected from the group consisting of alcohols and esters maybe present. The buprenorphine is in mixture with, e.g., dissolved in,the carboxylic acid, e.g., the levulinic acid, and this mixture, e.g.,solution, is dispersed in the form of small deposits, e.g., droplets, inthe matrix layer. Buprenorphine, with its known physicochemicalproperties, namely its poor solubility, its comparatively high meltingpoint of 216° C., and its high molecular weight, tends readily towardscrystallization. For this reason, a solubilizer with at least one acidicgroup (alternatively with an alcoholic or ester group) is used in orderto prevent the buprenorphine from crystallizing during the storage ofthe pharmaceutical form. Buprenorphine and levulinic acid have anextremely low solubility in polysiloxanes. As a consequence of this, itis possible to solubilize buprenorphine in levulinic acid and todisperse this mixture in the form of small deposits (e.g. droplets) in amatrix layer prepared on the basis of polysiloxanes as described herein.

Levulinic acid is sparingly soluble in the organic solvents of theadhesives. Consequently, the liquid mixture of buprenorphine andlevulinic acid can be dispersed in the solution of the adhesive, withthe dispersion being retained following removal of the solvent. In amatrix layer of this kind, the solubility of the buprenorphine isdependent virtually only on the amount of the levulinic acid.

The amount of the dispersed mixture of buprenorphine, e.g.,buprenorphine base, and the carboxylic acid, e.g., levulinic acid, canbe up to about 40% by weight, it being preferred not to exceed about 25%or about 20% by weight and ranges from about 15% to about 25%, or fromabout 15% to about 20%, or from about 17% to about 20%. The size of thedeposit, e.g., droplet (diameter) itself ought preferably not to exceedabout 150 μm, or ranges from about 1 to about 150 μm, preferably fromabout 1 to about 50 μm, or from about 5 to about 50 μm, or from about 1to about 25 μm or from about 5 to about 25 μm. The preferred size isdependent, furthermore, on the thickness of the matrix layer.

Since the carboxylic acid, e.g., the levulinic acid, can likewise beabsorbed through the skin, the amount in the TTS becomes less as thetime of application elapses, and leads to a reduction of the solubilityof buprenorphine. As a result, the decrease in the thermodynamicactivity of buprenorphine due to depletion is compensated by the reduceddrug solubility in the buprenorphine/levulinic acid deposits.

According to the invention the dry buprenorphine-containingpressure-sensitive adhesive layer contains more than about 5%, or morethan about 6%, or more than about 7%, or more than about 8%, or morethan about 9%, or from about 6% to about 20%, or from about 7% to about20%, or from about 8 to about 20%, or from about 9 to about 20%, or fromabout 5% to about 15%, or from about 6% to about 15%, or from about 6%to about 9%, or from about 9% to about 15% carboxylic acid, e.g.,levulinic acid based on the total dry weight of the drybuprenorphine-containing pressure-sensitive adhesive layer. In aspecific embodiment the dry buprenorphine-containing pressure-sensitiveadhesive layer contains from about 6% to about 11% levulinic acid, orfrom about 6% to about 9% or from about 9% to about 15% levulinic acid,or about 7% levulinic acid or about 10% levulinic acid. According to aspecific embodiment the pressure-sensitive adhesive layer contains thesame %-amount of levulinic acid and buprenorphine base or equimolaramounts of pharmaceutically acceptable salts. According to anotherspecific embodiment, the pressure-sensitive adhesive layer contains less%-amount of levulinic acid than it contains %-amount of buprenorphinebase or equimolar amounts of pharmaceutically acceptable salts.

According to a specific embodiment, the pressure-sensitive adhesivelayer contains more than about 9% to about 15% buprenorphine base andfrom about 6% to about 9% levulinic acid or from more than about 9% toabout 15% buprenorphine base, and from about 9% to about 15% levulinicacid based on the total dry weight.

According to a certain embodiment, the pressure-sensitive adhesive layeris coated at a dry weight of from about 10 mg/cm² to about 14 mg/cm², orfrom about 11.5 mg/cm² to about 12.5 mg/cm², or is about 12 mg/cm², andthe dry pressure-sensitive adhesive layer contains from about 7% toabout 13% or from about 8% to about 12%, or from about 9% to about 11%or about 10% buprenorphine base and from about 6% to about 8%, or about7% levulinic acid. In a specific embodiment the dry pressure-sensitiveadhesive layer has a dry weight of about 12 mg/cm² and contains about 7%levulinic acid and about 10% buprenorphine base.

According to a certain other embodiment, the pressure-sensitive adhesivelayer is coated at a dry weight of from about 10 mg/cm² to about 14mg/cm², or from about 11.5 mg/cm² to about 12.5 mg/cm², or is about 12mg/cm², and the dry pressure-sensitive adhesive layer contains fromabout 7% to about 13% or from about 8% to about 12%, or from about 9% toabout 11% or about 10% buprenorphine base and from about 8 to about 12%or about 10% levulinic acid. In a specific embodiment, the drypressure-sensitive adhesive layer has a dry weight of about 12 mg/cm²,and contains about 10% levulinic acid and about 10% buprenorphine base.

In accordance with the above, the TTS contains more than about 0.55mg/cm², or more than about 0.6 mg/cm², or more than about 0.7 mg/cm², ormore than about 0.8 mg/cm², or more than about 0.9 mg/cm², or more thanabout 1 mg/cm², or more than about 1.1 mg/cm² buprenorphine base or fromabout 0.6 mg/cm² to about 2 mg/cm², or from about 0.7 mg/cm² to about 2mg/cm², or from about 0.8 mg/cm² to about 2 mg/cm², or from about 0.9mg/cm² to about 2 mg/cm², or from about 1 mg/cm² to about 2 mg/cm², orfrom about 1.1 mg/cm² to about 2 mg/cm² buprenorphine base or containsabout 1.2 mg/cm² buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof. In certain embodiments,buprenorphine base is preferred. According to a specific embodiment, thepressure-sensitive adhesive layer contains the same amounts of levulinicacid and buprenorphine base. According to another specific embodiment,the pressure-sensitive adhesive layer contains less levulinic acid thanit contains buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof

According to a certain embodiment of the invention, thepressure-sensitive adhesives in the buprenorphine-containing layer andin the active agent-free layer are different, and the adhesive in theactive agent-free layer is a pressure-sensitive adhesive based onpolyacrylates. According to certain other embodiments, the adhesive inthe active agent-containing and the active agent-free layer are the sameand are an amine-resistant pressure-sensitive adhesive based onpolysiloxane. According to certain embodiments, the polysiloxane is aproduct of the condensation reaction of silanol endblockedpolydimethylsiloxane with a silica resin and the residual silanolfunctionality is capped with trimethylsiloxy groups and characterized bya solution viscosity at 25° C. and about 60% solids content in heptanesof about 500 mPa s or of about 450 mPa s. According to certainembodiments, the buprenorphine-containing pressure-sensitive adhesivelayer is coated at a dry weight of about 12 mg/cm² and contains about10% buprenorphine base and about 10% levulinic acid.

According to certain embodiments, the area of release ranges from about1 cm² to about 38 cm², or is less than 25 cm², or less than 22 cm², orranges from about 1.5 to about 25 cm², or from about 1.5 to about 22cm², or from about 1.5 to about 20 cm², or is about 3 cm², or about 6cm², or about 10 cm², or about 15 cm² or about 20 cm².

According to certain embodiments, the TTS contains from about 1 mg toabout 32 mg of buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof, or from about 1 mg to about 28mg, or from about 2 mg to about 25 mg, or from about 2 mg to about 24 mgof buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof. Considering five different increasing dosagestrengths, the TTS in specific cases preferably contains

-   -   a) from about 1 mg to about 4 mg, or from about 1 mg to about        4.5 mg, preferably from about 1 mg to about 3.5 mg, or from        about 2 mg to about 4 mg, more preferably from about 1 mg to        about 3 mg, or from about 2.5 mg to about 4 mg, or about 3 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   b) from about 3.5 mg to about 8 mg, or from about 4 mg to about        9 mg, preferably from about 3.5 mg to about 7 mg, or from about        5 mg to about 8 mg, more preferably from about 3.5 mg to about 6        mg, or from about 5 mg to about 7 mg, or about 6 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   c) from about 6.5 mg to about 16 mg, or from about 8 mg to about        14 mg, preferably from about 6.5 mg to about 14 mg, or from        about 10 mg to about 14 mg, more preferably from about 6.5 mg to        about 11 mg, or from about 11 mg to about 13 mg, or about 12 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   d) from about 11.5 mg to about 24 mg, or from about 15 mg to        about 20 mg, preferably from about 11.5 mg to about 21 mg, or        from about 16 mg to about 19 mg, more preferably from about 11.5        mg to about 14 mg, or from about 17 mg to about 19 mg, or about        18 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof, or    -   e) from about 15 mg to about 32 mg, or from about 20 mg to about        28 mg, preferably from about 15 mg to about 28 mg, or from about        21 mg to about 26 mg, more preferably from about 15 mg to about        24 mg, or from about 22 mg to about 25 mg, or about 24 mg of        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof.        Correspondingly the area of release ranges from about 1 cm² to        about 38 cm², or from 1.5 cm² to about 24 cm², or ranges from        1.5 cm² to about 22 cm², or ranges from 1.5 cm² to about 20 cm²        and with respect to the five specific preferred dosage        strengths a) to e)    -   a) ranges from about 1 cm² to about 4.8 cm², or from about 1.5        cm² to about 5.5 cm², preferably from about 1 cm² to about 4.5        cm², or from about 2 cm² to about 4 cm², more preferably from        about 2.5 cm² to about 4 cm², or from about 2 cm² to about 3        cm², or is about 2.5 cm², or    -   b) ranges from about 3 cm² to about 9.5 cm², or from about 3 cm²        to about 9 cm², preferably from about 3 cm² to about 9 cm², or        from about 4.5 cm² to about 7.5 cm², more preferably from about        5 cm² to about 8 cm², or from about 4.5 cm² to about 6 cm², or        is about 5 cm², or    -   c) ranges from about 6 cm² to about 19 cm², or from about 6 cm²        to about 14 cm², preferably from about 6 cm² to about 18 cm², or        from about 8 cm² to about 12 cm², more preferably from about 10        cm² to about 16 cm², or from about 9 cm² to about 11 cm², or is        about 10 cm², or    -   d) ranges from about 12 cm² to about 28.5 cm², or from about 13        cm² to about 17 cm², preferably from about 12 cm² to about 27        cm², or from about 13 cm² to about 16 cm², more preferably from        about 17 cm² to about 23 cm², or from about 14 cm² to about 16        cm², or is about 15 cm², or    -   e) ranges from about 16 cm² to about 38 cm², or from about 16        cm² to about 24 cm², preferably or from about 16 cm² to about 35        cm², or from about 17 cm² to about 22 cm², more preferably from        about 23.5 cm² to about 32 cm², or from about 18 cm² to about 21        cm², or is about 20 cm².        -   A further TTS providing a dosage strength between            strength b) and c) contains from about 5.5 mg to about 13 mg            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof and the area of            release ranges from about 5 cm² to about 14 cm², preferably            from about 5 cm² to about 13.5 cm².            In such embodiments the dry pressure-sensitive adhesive            layer preferably comprises a pressure-sensitive adhesive            based on polysiloxanes and has preferably a dry weight of            about 6 mg/cm², 7.5 mg/cm², 8 mg/cm², 9 mg/cm², 10.5 mg/cm²,            or 12 mg/cm² and contains 10% buprenorphine base.

According to certain preferred embodiments, the TTS contains withrespect to five dosage strengths a) to e) the following amounts ofbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides the following corresponding area ofrelease ranges:

a) about 1 cm² to about 1 cm² to about 2.5 cm² to a) about 4.8 cm² about4.5 cm² about 4 cm² about 1 X X X mg to about 4 mg about 1 X X X mg toabout 3.5 mg about 1 X X X mg to about 3 mg

b) about 3 cm² to about 3 cm² to about 5 cm² to b) about 9.5 cm² about 9cm² about 8 cm² about 3.5 X X X mg to about 8 mg about 3.5 X X X mg toabout 7 mg about 3.5 X X X mg to about 6 mg

c) about 6 cm² to about 6 cm² to about 10 cm² to c) about 19 cm² about18 cm² about 16 cm² about 6.5 X X X mg to about 16 mg about 6.5 X X X mgto about 14 mg about 6.5 X X X mg to about 11 mg

d) about 12 cm² to about 12 cm² to about 17 cm² to d) about 28.5 cm²about 27 cm² about 23 cm² about 11.5 X X X mg to about 24 mg about 11.5X X X mg to about 21 mg about 11.5 X X X mg to about 14 mg

e) about 16 cm² to about 16 cm² to about 23.5 cm² to e) about 38 cm²about 35 cm² about 32 cm² about 15 X X X mg to about 32 mg about 15 X XX mg to about 28 mg about 15 X X X mg to about 24 mgThe further TTS providing the dosage strength between strength b) and c)provides from about 5.5 mg to about 13 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof and thearea of release ranges from about 5 cm² to about 14 cm², orfrom about 5.5 mg to about 13 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof and the area ofrelease ranges from about 5 cm² to about 13.5 cm².

Set of Transdermal Therapeutic Systems

For the treatment of pain a patient needs to be titrated to theindividual dose of buprenorphine to adequately control the pain. Inorder to meet the individual requirements five different dosagestrengths are provided in accordance with the invention.

According to one aspect, the invention relates to a set of two (firstand second, or second and third, or third and fourth, or fourth andfifth TTS, or any other combination of two of the five different dosagestrengths), three (first to third, or second to fourth or third to fifthTTS, or any other combination of three of the five different dosagestrengths), four (first to fourth or second to fifth TTS, or any othercombination of four of the five different dosage strengths) or five(first to fifth TTS) different transdermal therapeutic systems inaccordance with the invention, wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.8 cm², or from about1.5 cm² to about 5.5 cm² and contains an amount of said buprenorphinefrom about 1 mg to about 4 mg, or from about 1 mg to about 4.5 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9.5 cm², or from about3 cm² to about 9 cm² and contains an amount of said buprenorphine fromabout 3.5 mg to about 8 mg, or from about 4 mg to about 9 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm², or from about6 cm² to about 14 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 16 mg, or from about 8 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 28.5 cm², or fromabout 13 cm² to about 17 cm² and contains an amount of saidbuprenorphine from about 11.5 mg to about 24 mg, or from about 15 mg toabout 20 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm², or from about16 cm² to about 24 cm² and contains an amount of said buprenorphine fromabout 15 mg to about 32 mg, or from about 20 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof. The set of two to five different transdermaltherapeutic systems in accordance with this paragraph can be expanded byone or more further transdermal therapeutic system(s) which may providesmaller, greater or intermediate areas of release and amounts ofbuprenorphine compared with the five different transdermal therapeuticsystems described above, preferably the set of two to five differenttransdermal therapeutic systems is expanded by a further transdermaltherapeutic system which provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 14 cm² and contains anamount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, providing an intermediate transdermaltherapeutic system between the second and the third transdermaltherapeutic system. Alternatively, one of the transdermal therapeuticsystems of the set of two to five different transdermal therapeuticsystems can be replaced by such a further transdermal therapeuticsystem.

The invention relates also to set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.5 cm², or from about2 cm² to about 4 cm² and contains an amount of said buprenorphine fromabout 1 mg to about 4 mg, or from about 1 mg to about 3.5 mg, or fromabout 2 mg to about 4 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm², or from about4.5 cm² to about 7.5 cm² and contains an amount of said buprenorphinefrom about 3.5 mg to about 8 mg, or from about 3.5 mg to about 7 mg, orfrom about 5 mg to about 8 mg buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 18 cm², or from about8 cm² to about 12 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 16 mg, or from about 6.5 mg to about 14 mg, orfrom about 10 mg to about 14 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 27 cm², or from about13 cm² to about 16 cm² and contains an amount of said buprenorphine fromabout 11.5 mg to about 21 mg, or from about 11.5 mg to about 24 mg, orfrom about 16 mg to about 19 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 35 cm², or from about17 cm² to about 22 cm² and contains an amount of said buprenorphine fromabout 15 mg to about 32 mg, or from about 15 mg to about 28 mg, or fromabout 21 mg to about 26 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof. The set of two to fivedifferent transdermal therapeutic systems in accordance with thisparagraph can be expanded by one or more further transdermal therapeuticsystem(s) which may provide smaller, greater or intermediate areas ofrelease and amounts of buprenorphine compared with the five differenttransdermal therapeutic systems described above, preferably the set oftwo to five different transdermal therapeutic systems is expanded by afurther transdermal therapeutic system which provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 13.5 cm² and containsan amount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, providing an intermediate transdermaltherapeutic system between the second and the third transdermaltherapeutic system. Alternatively, one of the transdermal therapeuticsystems of the set of two to five different transdermal therapeuticsystems can be replaced by such a further transdermal therapeuticsystem.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2.5 cm² to about 4 cm², or from about2 cm² to about 3 cm² and contains an amount of said buprenorphine fromabout 1 mg to about 3 mg, or from about 2.5 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 8 cm², or from about4.5 cm² to about 6 cm² and contains an amount of said buprenorphine fromabout 3.5 mg to about 6 mg, or from about 5 mg to about 7 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 10 cm² to about 16 cm², or from about9 cm² to about 11 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 11 mg, or from about 11 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 23 cm², or from about14 cm² to about 16 cm² and contains an amount of said buprenorphine fromabout 11.5 mg to about 14 mg, or from about 17 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 23.5 cm² to about 32 cm², or fromabout 18 cm² to about 21 cm² and contains an amount of saidbuprenorphine from about 15 mg to about 24 mg, or from about 22 mg toabout 25 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof. The set of two to fivedifferent transdermal therapeutic systems in accordance with thisparagraph can be expanded by one or more further transdermal therapeuticsystem(s) which may provide smaller, greater or intermediate areas ofrelease and amounts of buprenorphine compared with the five differenttransdermal therapeutic systems described above, preferably the set oftwo to five different transdermal therapeutic systems is expanded by afurther transdermal therapeutic system which provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 13.5 cm² and containsan amount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, providing an intermediate transdermaltherapeutic system between the second and the third transdermaltherapeutic system. Alternatively, one of the transdermal therapeuticsystems of the set of two to five different transdermal therapeuticsystems can be replaced by such a further transdermal therapeuticsystem.

In a further aspect of the invention a transdermal therapeutic systemselected from a set of transdermal therapeutic systems as described inthe previous paragraphs is provided wherein buprenorphine is present inthe form of buprenorphine base and wherein

the first transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 6.25 cm² and providing a nominal mean release rate ofabout 5 μg/hr over about 168 hours of administration,the second transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 12.5 cm² and providing a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration,the third transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 25 cm² and providing a nominal mean release rate ofabout 20 μg/hr over about 168 hours of administration,the fourth transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 37.5 cm² and providing a nominal mean release rate ofabout 30 μg/hr over about 168 hours of administration,the fifth transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 50 cm² and providing a nominal mean release rate ofabout 40 μg/hr over about 168 hours of administration,the further transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 18.75 cm² and providing a nominal mean release rate ofabout 15 μg/hr over about 168 hours of administration,wherein the reference product is prepared by the following steps:

-   -   1. mixing of 1,139 g of a 47.83% polyacrylate solution of a        self-crosslinked acrylate copolymer of 2-ethylhexyl acrylate,        vinyl acetate, acrylic acid (solvent: ethyl        acetate:heptanes:isopropanol:toluene:acetylacetonate in the        ratio of 37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl        oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g        of ethyl acetate, and 100 g of buprenorphine base to provide a        mixture;    -   2. stirring the mixture of step 1 for about 2 hours and        controlling the dissolution of all solids visually whereas        controlling the evaporation loss by reweighing and replenishing        the possible solvent loss by ethyl acetate;    -   3. subsequently applying the mixture on a transparent polyester        film in such a manner that the mass per unit area of the dry        adhesive layer amounts to about 80 g/m² wherein the polyester        film is rendered removable by means of siliconization and serves        as protective layer;    -   4. removing the solvents of the mixture applied on a transparent        polyester film in step 3 by drying with heated air which is led        over a moist lane resulting in evaporation of the solvents, but        also in melting of the levulinic acid and covering the adhesive        film with a polyester foil;    -   5. punching the area of release of 6.25 cm², 12.5 cm², 18.75        cm², 25 cm², 37.5 cm² and 50 cm², respectively, by means of        suitable cutting tools and removing the edges left between the        individual systems.

According to one aspect, the invention relates to a transdermaltherapeutic system described as first transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 6.25 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system described as second transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 12.5 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system described as third transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 25 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.8 cm² and containing anamount of said buprenorphine from 1 mg to about 4 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 5 μg/hr and/or providinga mean AUCt of more than 7,000 pg·hr/ml, preferably more than 8,000pg·hr/ml, or of from more than 7,000 pg·hr/ml to about 16,000 pg·hr/ml,or of from more than 8,000 pg·hr/ml to about 16,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9.5 cm² and containing anamount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 10 μg/hr and/or providing a mean AUCt of more than 14,000pg·hr/ml, preferably of more than 16,000 pg·hr/ml, or of from more than14,000 pg·hr/ml to about 32,000 pg·hr/ml, or of from more than 16,000pg·hr/ml to about 32,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 19 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr and/or providing a mean AUCt of more than 28,000pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 28.5 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr and/or providing a mean AUCt of more than 42,000pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 38 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr and/or providing a mean AUCt of more than 62,000pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda further transdermal therapeutic system providing a size of the area ofrelease ranging from about 5 cm² to about 14 cm² and containing anamount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 15 μg/hr and/or providing a mean AUCt of more than 22,000pg·hr/ml, preferably of more than 24,000 pg·hr/ml, or of from more than22,000 pg·hr/ml to about 48,000 pg·hr/ml, or of from more than 24,000pg·hr/ml to about 48,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.5 cm² and containing anamount of said buprenorphine from 1 mg to about 4 mg, or from 1 mg toabout 3.5 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 5 μg/hr and/or providing a mean AUCt of more than7,000 pg·hr/ml, preferably more than 8,000 pg·hr/ml, or of from morethan 7,000 pg·hr/ml to about 16,000 pg·hr/ml, or of from more than 8,000pg·hr/ml to about 16,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9 cm² and containing an amountof said buprenorphine from about 3.5 mg to about 8 mg, or from about 3.5mg to about 7 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 10 μg/hr and/or providing a mean AUCt of more than14,000 pg·hr/ml, preferably of more than 16,000 pg·hr/ml, or of frommore than 14,000 pg·hr/ml to about 32,000 pg·hr/ml, or of from more than16,000 pg·hr/ml to about 32,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 18 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 16 mg, or fromabout 6.5 mg to about 14 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 20 μg/hr and/or providing a mean AUCt of more than28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of frommore than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 27 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 24 mg, or fromabout 11.5 mg to about 21 mg buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof and providing a nominalmean release rate of about 30 μg/hr and/or providing a mean AUCt of morethan 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or offrom more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from morethan 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 35 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mg, or fromabout 15 mg to about 28 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 40 μg/hr and/or providing a mean AUCt of more than62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of frommore than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from morethan 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda further transdermal therapeutic system providing a size of the area ofrelease ranging from about 5 cm² to about 13.5 cm² and containing anamount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 15 μg/hr and/or providing a mean AUCt of more than 22,000pg·hr/ml, preferably of more than 24,000 pg·hr/ml, or of from more than22,000 pg·hr/ml to about 48,000 pg·hr/ml, or of from more than 24,000pg·hr/ml to about 48,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population.

According to one aspect, the invention relates a transdermal therapeuticsystem comprising buprenorphine for the transdermal administration ofbuprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 2.5 cm² to about 4 cm² and containing anamount of said buprenorphine from 1 mg to about 3 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 5 μg/hr and/or providinga mean AUCt of more than 7,000 pg·hr/ml, preferably more than 8,000pg·hr/ml, or of from more than 7,000 pg·hr/ml to about 16,000 pg·hr/ml,or of from more than 8,000 pg·hr/ml to about 16,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 5 cm² to about 8 cm² and containing an amountof said buprenorphine from about 3.5 mg to about 6 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 10 μg/hr and/or providinga mean AUCt of more than 14,000 pg·hr/ml, preferably of more than 16,000pg·hr/ml, or of from more than 14,000 pg·hr/ml to about 32,000 pg·hr/ml,or of from more than 16,000 pg·hr/ml to about 32,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 10 cm² to about 16 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 11 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr and/or providing a mean AUCt of more than 28,000pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 17 cm² to about 23 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr and/or providing a mean AUCt of more than 42,000pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 23.5 cm² to about 32 cm² and containing anamount of said buprenorphine from about 15 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr and/or providing a mean AUCt of more than 62,000pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; anda further transdermal therapeutic system providing a size of the area ofrelease ranging from about 5 cm² to about 13.5 cm² and containing anamount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 15 μg/hr and/or providing a mean AUCt of more than 22,000pg·hr/ml, preferably of more than 24,000 pg·hr/ml, or of from more than22,000 pg·hr/ml to about 48,000 pg·hr/ml, or of from more than 24,000pg·hr/ml to about 48,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population.

Release Characteristic

In accordance with the invention, the TTS is further characterized bythe skin permeation rate determined by in vitro experiments carried outwith the Franz diffusion cell (e.g., a 9 ml Franz diffusion cell), usinghuman split thickness skin. Skin from cosmetic surgeries (female breast,date of birth 1989) can be used. A dermatone is used to prepare skin toa thickness of 800 μm, with an intact epidermis, in accordance with theOECD Guideline (adopted Apr. 13, 2004). Due to the prolonged test (168hours) 800 μm skin is used instead of the recommended 200 to 400 μmskin. The receptor medium used is a phosphate buffer solution pH 5.5with 0.1% saline azide as antibacteriological agent is used at atemperature of 32±1°. Example formulations with an area of 1.163 cm² arepunched from laminates, and in the present examples are each testedagainst 1.163 cm² samples of the commercial product Norspan®. Theconcentrations of buprenorphine in the acceptor medium of the Franz cellare measured.

The TTS according to the invention provides a mean cumulative skinpermeation rate of more than about 1.3 μg/cm²-hr, or more than about 1.5μg/cm²-hr or more than about 1.7 μg/cm²-hr over a 168 hours test, or ofmore than about 2 μg/cm²-hr over a 168 hours test, or of more than about2.5 μg/cm²-hr over a 168 hours test, or of more than 2.7 μg/cm²-hr overa 168 hours test, or of more than about 3 μg/cm²-hr over a 168 hourstest, or from about 1.3 μg/cm²-hr to about 4 μg/cm²-hr, or from about1.7 μg/cm²-hr to about 4 μg/cm²-hr, or from about 2 μg/cm²-hr to about 4μg/cm²-hr, or from about 2.5 μg/cm²-hr to about 4 μg/cm²-hr, or fromabout 2.7 μg/cm²-hr to about 4 μg/cm²-hr, or from about 3 μg/cm²-hr toabout 4 μg/cm²-hr, over a 168 hours test. The commercial productBuTrans® provides a mean cumulative skin permeation rate of about 1.7μg/cm²-hr over a 168 hours test in said test.

According to certain embodiments, the TTS provides a cumulative releaseas measured in a Franz diffusion cell as mentioned above of about 220μg/cm² to about 640 μg/cm² over a time period of 168 hours, or of about400 μg/cm² to about 640 μg/cm², or of about 450 μg/cm² to about 640μg/cm², or of about 500 μg/cm² to about 640 μg/cm², or of about 600μg/cm² to about 640 μg/cm² over a time period of 168 hours. Thecommercial product BuTrans® provides a cumulative release of about 250.7μg/cm² in said test. As can be seen from FIG. 13, comparable skinpermeation rates are measured using the 25 cm² BuTrans® TTS including 20mg buprenorphine base and a TTS of an example in accordance with theinvention with an area of 14 cm² and including 12.6 mg buprenorphinebase. This corresponds to about a 44% size reduction in area of releaseand a reduction of about 50% in the amount of used buprenorphine base.

According to certain embodiments, the TTS provides a non-cumulativerelease of buprenorphine base as measured in a Franz diffusion cell of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

According to certain embodiments, the TTS provides a non-cumulativerelease of buprenorphine base as measured in a Franz diffusion cell of

2 μg/cm² to 6 μg/cm² in the first 8 hours,25 μg/cm² to 60 μg/cm² from hour 8 to hour 24,25 μg/cm² to 60 μg/cm² from hour 24 to hour 32,40 μg/cm² to 100 μg/cm² from hour 32 to hour 48,50 μg/cm² to 140 μg/cm² from hour 48 to hour 72,100 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

According to certain embodiments, the TTS provides a non-cumulativerelease of buprenorphine base as measured in a Franz diffusion cell of

3 μg/cm² to 6 μg/cm² in the first 8 hours,30 μg/cm² to 50 μg/cm² from hour 8 to hour 24,30 μg/cm² to 50 μg/cm² from hour 24 to hour 32,60 μg/cm² to 90 μg/cm² from hour 32 to hour 48,100 μg/cm² to 130 μg/cm² from hour 48 to hour 72,200 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and60 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

The commercial product BuTrans® provides a non-cumulative release ofbuprenorphine base as measured in a Franz diffusion cell in the samesetting of

2.1 μg/cm² in the first 8 hours,25.2 μg/cm² from hour 8 to hour 24,19.4 μg/cm² from hour 24 to hour 32,34.3 μg/cm² from hour 32 to hour 48,48.2 μg/cm² from hour 48 to hour 72,92.7 μg/cm² from hour 72 to hour 144, and28.5 μg/cm² from hour 144 to hour 168.

Method of Treatment/Medical Use

According to one aspect, the transdermal therapeutic system inaccordance with the invention and as described above in detail is foruse in a method of treating pain. The Method comprises in particular theapplication of the TTS for about 168 hours (corresponding to 7 days orone week) on the skin of a patient. According to other methods inaccordance with the invention the TTS can be applied for more than about96 hours corresponding to more than 4 days, or about 120 hourscorresponding to 5 days and about 144 hours corresponding to 6 days. Theapplication for about 168 hours is preferred.

According to one aspect, the invention relates to a method of treatmentwherein a set of five different transdermal therapeutic systemscorresponding to different dosage strengths and corresponding differentnominal mean release rates and/or mean release rates over about 168hours of administration is used, wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1.5 cm² to about 5.5 cm² and containsan amount of said buprenorphine from about 1 mg to about 4.5 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4to about 6 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 5 μg/hr over about 168 hours of administration;andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm² and contains anamount of said buprenorphine from about 4 mg to about 9 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof and provides a mean release rate of buprenorphine ranging fromabout 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/orprovides a nominal mean release rate of buprenorphine of about 10 μg/hrover about 168 hours of administration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 14 cm² and contains anamount of said buprenorphine from about 8 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/hr over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 13 cm² to about 17 cm² and containsan amount of said buprenorphine from about 15 mg to about 20 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 30 μg/hr over about 168 hours of administration;andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 24 cm² and containsan amount of said buprenorphine from about 20 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

The invention relates also to set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2 cm² to about 4 cm² and contains anamount of said buprenorphine from about 2 mg to about 4 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof and provides a mean release rate of buprenorphine ranging fromabout 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/orprovides a nominal mean release rate of buprenorphine of about 5 μg/hrover about 168 hours of administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 4.5 cm² to about 7.5 cm² and containsan amount of said buprenorphine from about 5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 8 to about 12 μg/hr or from about 9 toabout 11 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 10 μg/hr over about 168 hours of administration;andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 8 cm² to about 12 cm² and contains anamount of said buprenorphine from about 10 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/hr over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 13 cm² to about 16 cm² and containsan amount of said buprenorphine from about 16 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 30 μg/hr over about 168 hours of administration;andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 22 cm² and containsan amount of said buprenorphine from about 21 mg to about 26 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2 cm² to about 3 cm² and contains anamount of said buprenorphine from about 2.5 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4to about 6 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 5 μg/hr over about 168 hours of administration;andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 4.5 cm² to about 6 cm² and containsan amount of said buprenorphine from about 5 mg to about 7 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 8 to about 12 μg/hr or from about 9 toabout 11 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 10 μg/hr over about 168 hours of administration;andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 9 cm² to about 11 cm² and contains anamount of said buprenorphine from about 11 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/rh over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 14 cm² to about 16 cm² and containsan amount of said buprenorphine from about 17 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, or about 30 μg/hr over about 168 hours ofadministration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 18 cm² to about 21 cm² and containsan amount of said buprenorphine from about 22 mg to about 25 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

According to one aspect, the invention relates to a method of treatingpain in a patient wherein said patient is treated with one appropriatelyselected TTS from a set of two (first and second, or second and third,or third and fourth, or fourth and fifth TTS, or any other combinationof two of the five different dosage strengths), three (first to third,or second to fourth or third to fifth TTS, or any other combination ofthree of the five different dosage strengths), four (first to fourth orsecond to fifth TTS, or any other combination of four of the fivedifferent dosage strengths) or five (first to fifth TTS) differenttransdermal therapeutic systems corresponding to different dosagestrengths and corresponding different nominal mean release rates and/ormean release rates over about 168 hours of administration is used,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.8 cm² and containsan amount of said buprenorphine from about 1 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 2 μg/hr, or of from about 2.5 to about7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 5 μg/hr over about 168 hoursof administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9.5 cm² and containsan amount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 6 μg/hr, or of from about 8 to about 12μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal meanrelease rate of buprenorphine of about 10 μg/hr over about 168 hours ofadministration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm² and contains anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 15 to about25 μg/hr or at least about 16 μg/hr, or from about 17 to about 22 μg/hr,and/or provides a nominal mean release rate of buprenorphine of about 20μg/hr over about 168 hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 28.5 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 21 μg/hr, or of from about 26 to about35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 30 μg/hr over about 168hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm² and containsan amount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 31 μg/hr, or of from about 36 to about45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 40 μg/hr over about 168hours of administration. The set of two to five different transdermaltherapeutic systems in accordance with this paragraph can be expanded bya further transdermal therapeutic system which provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 14 cm² and contains anamount of said buprenorphine from about 5.5 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 12 to about18 μg/hr or from about 13.5 to about 16.5 μg/hr, and/or provides anominal mean release rate of buprenorphine of about 15 μg/hr over about168 hours of administration. Alternatively, one of the transdermaltherapeutic systems of the set of two to five different transdermaltherapeutic systems can be replaced by said transdermal therapeuticsystem.

The invention relates also to a set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.5 cm² and containsan amount of said buprenorphine from about 1 mg to about 4 mg, or fromabout 1 mg to about 3.5 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and provides a mean releaserate of buprenorphine of at least about 2 μg/hr, or of from about 2.5 toabout 7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides anominal mean release rate of buprenorphine of about 5 μg/hr over about168 hours of administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm² and contains anamount of said buprenorphine from about 3.5 mg to about 8 mg, or fromabout 3.5 mg to about 7 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and provides a mean releaserate of buprenorphine of at least about 6 μg/hr, or of from about 8 toabout 12 μg/hr or from about 9 to about 11 μg/hr, and/or provides anominal mean release rate of buprenorphine of about 10 μg/hr over about168 hours of administration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 18 cm² and contains anamount of said buprenorphine from about 6.5 mg to about 16 mg, or fromabout 6.5 mg to about 14 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and provides a mean releaserate of buprenorphine of at least about 11 μg/hr, or of from about 15 toabout 25 μg/hr or at least about 16 μg/hr, from about 17 to about 22μg/hr, and/or provides a nominal mean release rate of buprenorphine ofabout 20 μg/hr over about 168 hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 27 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 24 mg, orfrom about 11.5 mg to about 21 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof and provides a meanrelease rate of buprenorphine of at least about 21 μg/hr, or of fromabout 26 to about 35 μg/hr or from about 27 to about 32 μg/hr, and/orprovides a nominal mean release rate of buprenorphine of about 30 μg/hrover about 168 hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 35 cm² and containsan amount of said buprenorphine from about 15 mg to about 32 mg, or fromabout 15 mg to about 28 mg buprenorphine base or an equimolar amount ofa pharmaceutically acceptable salt thereof and provides a mean releaserate of buprenorphine of at least about 31 μg/hr, or of from about 36 toabout 45 μg/hr or from about 38 to about 42 μg/hr, and/or provides anominal mean release rate of buprenorphine of about 40 μg/hr over about168 hours of administration. The set of two to five differenttransdermal therapeutic systems in accordance with this paragraph can beexpanded by a further transdermal therapeutic system which provides asize of said buprenorphine-containing pressure-sensitive adhesive layerproviding the area of release ranging from about 5 cm² to about 13.5 cm²and contains an amount of said buprenorphine from about 5.5 mg to about13 mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 12 to about18 μg/hr or from about 13.5 to about 16.5 μg/hr, and/or provides anominal mean release rate of buprenorphine of about 15 μg/hr over about168 hours of administration. Alternatively, one of the transdermaltherapeutic systems of the set of two to five different transdermaltherapeutic systems can be replaced by said transdermal therapeuticsystem. Alternatively, one of the transdermal therapeutic systems of theset of two to five different transdermal therapeutic systems can bereplaced by said transdermal therapeutic system.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2.5 cm² to about 4 cm² and containsan amount of said buprenorphine from about 1 mg to about 3 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 2 μg/hr, or of from about 2.5 to about7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 5 μg/hr over about 168 hoursof administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 8 cm² and contains anamount of said buprenorphine from about 3.5 mg to about 6 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 6 μg/hr, or of from about 8 to about 12μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal meanrelease rate of buprenorphine of about 10 μg/hr over about 168 hours ofadministration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 10 cm² to about 16 cm² and containsan amount of said buprenorphine from about 6.5 mg to about 11 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 15 to about25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 20 μg/hr over about 168hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 23 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 21 μg/hr, or of from about 26 to about35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 30 μg/hr over about 168hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 23.5 cm² to about 32 cm² and containsan amount of said buprenorphine from about 15 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 31 μg/hr, or of from about 36 to about45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 40 μg/hr over about 168hours of administration.

According to one aspect, the invention relates to a method of treatingpain in a patient wherein a patient is treated with one appropriatelyselected TTS from a set of different transdermal therapeutic systems asdescribed in the previous paragraphs, wherein:

the first transdermal therapeutic system provides a mean AUCt of morethan 7,000 pg·hr/ml, preferably more than 8,000 pg·hr/ml, or of frommore than 7,000 pg·hr/ml to about 16,000 pg·hr/ml, or of from more than8,000 pg·hr/ml to about 16,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe second transdermal therapeutic system provides a mean AUCt of morethan 14,000 pg·hr/ml, preferably of more than 16,000 pg·hr/ml, or offrom more than 14,000 pg·hr/ml to about 32,000 pg·hr/ml, or of from morethan 16,000 pg·hr/ml to about 32,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe third transdermal therapeutic system provides a mean AUCt of morethan 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or offrom more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from morethan 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe fourth transdermal therapeutic system provides a mean AUCt of morethan 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or offrom more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from morethan 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe fifth transdermal therapeutic system provides a mean AUCt of morethan 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or offrom more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of frommore than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation; andthe further transdermal therapeutic system provides a mean AUCt of morethan 22,000 pg·hr/ml, preferably of more than 24,000 pg·hr/ml, or offrom more than 22,000 pg·hr/ml to about 48,000 pg·hr/ml, or of from morethan 24,000 pg·hr/ml to about 48,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation.

According to one aspect, the invention relates to a method of treatmentdescribed in the previous paragraphs, wherein the transdermaltherapeutic system provides a mean AUCt per area of release of more than1,700 pg·hr/ml-cm², or of more than 1,900 pg·hr/ml-cm², or of more than2,300 pg·hr/ml-cm² over about 168 hours of administration after asingle-dose administration to a subject population or provides a meanAUCt per area of release of from more than 1,700 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm², or of from more than 1,900 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm², or of from more than 2,300 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm² over about 168 hours of administration after asingle-dose administration to a subject population.

According to one aspect, the invention relates to a method of treatmentdescribed in the previous paragraphs, wherein the transdermaltherapeutic system provides an arithmetic mean tmax of from about 60 hrto about 120 hr, preferably from about 66 hr to less than 108 hr, orfrom about 72 hr to about 96 hr after a single-dose administration to asubject population.

Method of Manufacture

According to one further aspect, the invention relates to a method ofmanufacture of a transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising the steps of

1. providing a buprenorphine-containing adhesive mixture comprising

a) buprenorphine base or a pharmaceutically acceptable salt thereof

b) a carboxylic acid (e.g., levulinic acid),

c) a viscosity increasing agent (e.g. polyvinylpyrrolidone)

c) a polymer-based pressure-sensitive adhesive, and

d) solvent (e.g., heptane and ethanol)

2. storing said mixture between 0 hours and 6 days3. homogenizing said buprenorphine-containing adhesive mixture at ahomogenizing speed of e.g. at least 1000 rpm (e.g. with a BECOMIX RW 30Ex);4. storing said homogenized mixture between 0 hours and 6 days,5. coating said homogenized buprenorphine-containing adhesive mixture ona film (e.g., polyethylene terephthalate film) in an amount to providethe desired dry weight using a roller coater in an amount to provide thedesired coating dry weight,6. drying said coated buprenorphine-containing adhesive mixture toprovide a buprenorphine-containing adhesive layer with the desiredcoating dry weight,7. optionally laminating said buprenorphine-containing adhesive layer toa backing layer (e.g., Scotchpak 1220 from 3M) to provide anbuprenorphine-containing self-adhesive layer structure,8. optionally punching the individual systems from thebuprenorphine-containing self-adhesive layer structure with the desiredarea of release, and9. optionally adhering to the individual systems an active-freeself-adhesive layer structure comprising also a backing layer and anactive agent-free pressure-sensitive adhesive layer and which is largerthan the individual systems of buprenorphine-containing self-adhesivelayer structure.

In step 1 of said method of manufacture preferably buprenorphine base,levulinic acid and polyvinylpyrrolidone are used and are dissolved inethanol and subsequently suspended in a polymer-based pressure-sensitiveadhesive based on polysiloxane in heptane to provide thebuprenorphine-containing adhesive mixture or emulsion.

The homogenization provides homogeneous mixtures and helps to providenarrower deposit size distributions. In combination with aviscositiy-increasing substance in the deposits the size and sizedistribution of the deposits remains during the time betweenhomogenization and coating and during coating. In particular the processis suitable for a commercial production scale.

Homogenization speeds of e.g. at least 1000 rpm can be applied with ahomogenizer, e.g. with a rotor-stator homogenizer (e.g. BECOMIX RW 30Ex). In certain embodiments of the invention the homogenization speed isfrom about 1500 rpm to about 3800 rpm, or from about 1500 rpm to about3000 rpm. The preferred homogenization speed is about 2000 rpm.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention.

Comparative Example 1

The composition of the buprenorphine base-containing adhesive mixture issummarized in Table 1 below.

TABLE 1 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 7.00Levulinic acid 4.90 Ascorbyl palmitate 0.175 Ethanol 3.80 Polysiloxaneadhesive in n-heptane 79.57 Solids content of 73% by weight (BIO-PSA7-4201 from Dow Corning Healthcare) n-heptane 4.56 Total 100.01

In a suitable vessel, 7.00 g of buprenorphine were dissolved in 4.90 gof levulinic acid, 3.80 g of Ethanol and 0.175 g of Ascobyl palmitate bystirring until the buprenorphine was completely dissolved forming thebuprenorphine solution. 79.57 g of a polysiloxane adhesive in the formof a solution in n-heptane having a solids content of 73% by weight and4.56 g of heptane were added. The mixture was stirred to give 100.01 gof a buprenorphine-containing adhesive mixture with 7% of buprenorphine,with a solids content of 70% (buprenorphine base-containing adhesivemixture).

The buprenorphine base-containing adhesive mixture was coated withinless than 24 h after the buprenorphine containing mixture was finishedon a polyethylene terephthalate film (e.g. Scotchpak from 3M) using anErichsen coater and the solvent was removed by drying at approximately50° C. for approx. 8 minutes.

The coating thickness was chosen such that removal of the solventsresults in a coating weight of the matrix layer of approx. 120 g/m².This results in the 10% by weight of buprenorphine base, and 7% byweight of levulinic acid in this matrix layer. The dried film waslaminated with the backing layer (e.g. polyethylenterephthalate (PET)foil 19 μm) to provide the buprenorphine-containing self-adhesive layerstructure.

Microscopic pictures were taken of the matrix layer using a Nikon S/N237789 Microscope. FIG. 1 shows a microscopic picture of the matrixlayer of Example 1.

Comparative Example 2

The composition of the buprenorphine base-containing adhesive mixture issummarized in Table 2 below.

TABLE 2 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.890Levulinic acid 1.323 Ethanol 0.945 Polysiloxane adhesive in n-heptane21.489 Solids content of 73% by weight (BIO-PSA 7-4201 from Dow CorningHealthcare) n-heptane 1.353 Total 27

In a stainless steel vessel, 1.890 kg of buprenorphine were dissolved in1.323 kg of levulinic acid and 0.945 kg of ethanol by stirring until thebuprenorphine was completely dissolved. With stirring, 21.489 kg of apolysiloxane adhesive in the form of a solution in n-heptane having asolids content of 73% by weight and 1.353 kg of heptane were added. Themixture was stirred to give 27 kg of a buprenorphine-containing adhesivemixture with 7% of buprenorphine, with a solids content of 70%(buprenorphine base-containing adhesive mixture).

Within 24 hours the buprenorphine base-containing adhesive mixture wascoated on a polyethylene terephthalate film (e.g., Scotchpak from 3M)using a pilot plant roll coater including a drying tunnel, severaldrying sections, an unwinding and laminating station. The solvent wasremoved by drying at approximately 30-50° C. The matrix layer remainedwithin the drying tunnel at approx. 8 minutes. The coating thickness waschosen such that removal of the solvents results in a coating weight ofthe matrix layer of 120 g/m². This results in the 10% by weight ofbuprenorphine base and 7% by weight of levulinic acid in this matrixlayer. The dried film was laminated with the backing layer (e.g:polyethylenterephthalate (PET) film 19 μm) to provide thebuprenorphine-containing self-adhesive layer structure.

The individual systems (TTS) were then punched from thebuprenorphine-containing self-adhesive layer structure.

In specific embodiments a TTS as described above can be provided with afurther self-adhesive layer of larger surface area, preferably withrounded corners, comprising a pressure-sensitive adhesive matrix layerwhich is free of active ingredient and has a preferably beige coloredbacking layer (overtape). This is of advantage when the TTS, on thebasis of its physical properties alone, does not adhere sufficiently tothe skin and/or when the buprenorphine-containing matrix layer, for thepurpose of avoiding waste, has pronounced corners (square or rectangularshapes). The overtape including the TTS are then punched out by onlypunching the overtape and sealed into pouches of the primary packagingmaterial.

Microscopic pictures were taken of the buprenorphine base-containingadhesive mixture and of the matrix layer using a Nikon S/N 237789Microscope. FIG. 2A shows a microscopic picture of the buprenorphinebase-containing adhesive mixture of Comparative Example 2 and FIG. 2Bshows a microscopic picture of the matrix layer of Comparative Example2.

Example 3

The composition of the buprenorphine base-containing adhesive mixture issummarized in Table 3 below.

TABLE 3 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 7.44Levulinic acid 5.24 Ascorbyl palmitate 0.14 Polyvinylpyrrolidone (PVP)1.88 Ethanol 10.77 Polysiloxane adhesive in n-heptane 82.47 Solidscontent of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare)n-heptane 1.73 Total 109.67

In a suitable vessel, 37.86 g of polyvinylpyrrolidone and 113.57 g ofethanol were dissolved to form a 25% PVP pre-solution. The prescribedamount of the PVP pre-solution, Levulinic acid and Ascorbyl palmitatewere suspended with stirring and afterwards the remaining part ofEthanol and the Buprenorphine was added to form a buprenorphinecontaining solution by stirring until a solution is formed. 82.50 g of apolysiloxane adhesive in the form of a solution in n-heptane having asolids content of 73% by weight and 1.74 g of heptane were added. Themixture was stirred to give 109.67 g of a buprenorphine-containingadhesive mixture with 6.8% of buprenorphine, with a solids content of68% (buprenorphine base-containing adhesive mixture).

The buprenorphine base-containing adhesive mixture was coated withinless than 24 h after the buprenorphine containing mixture was finishedon a polyethylene terephthalate film (e.g. Scotchpak from 3M) using anErichsen coater and the solvent was removed by drying in a first step atroom temperature for approximately 10 minutes, followed by a seconddrying step at approximately 60° C. for approx. 10 minutes.

The coating thickness was chosen such that removal of the solventsresults in a coating weight of the matrix layer of approx. 120 g/m².This results in the 10% by weight of buprenorphine base, 7% by weight oflevulinic acid and 2.5% by weight of polyvinylpyrrolidone in this matrixlayer. The dried film was laminated with the backing layer (e.g.polyethylenterephthalate (PET) foil 19 μm) to provide thebuprenorphine-containing self-adhesive layer structure.

Microscopic pictures were taken of the buprenorphine base-containingadhesive mixture and the matrix layer using a Nikon S/N 237789Microscope. FIG. 3 shows a microscopic picture of the matrix layer ofExample 3. FIG. 3A shows a microscopic picture of the buprenorphinebase-containing adhesive mixture of Example 3 and FIG. 3B shows amicroscopic picture of the matrix layer of Example 3.

Example 4

The composition of the buprenorphine base-containing adhesive mixture issummarized in Table 4 below.

TABLE 4 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.368Levulinic acid 0.958 Polyvinylpyrrolidone (PVP) 0.342 Ascorbyl palmitate0.027 Ethanol 1.938 Polysiloxane adhesive in n-heptane 15.048 Solidscontent of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare)n-heptane 0.319 Total 20

In a 10 l vessel, 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanolwere dissolved to form a 25% PVP pre-solution. In a homogenizing/mixingvessel: Becomix Lab mixer RW 30 Ex, 1.368 kg of PVP pre-solution, 0.958kg levulinic acid, 0.027 kg of Ascorbyl palmitate and the main part of0.912 kg of Ethanol were suspended by stirring. The prescribed amount ofbuprenorphine was weighed and added to the homogenizing/mixing vesselfollowed by rinsing the weighing container used for buprenorphine withthe remaining part of Ethanol. The mixture was kept under stirring forat least 1 h until a buprenorphine containing solution was formed.15.048 kg of a polysiloxane adhesive in the form of a solution inn-heptane having a solids content of 73% by weight and 0.319 kg ofn-heptane were added to the mixing/homogenizing vessel The mixture wasstirred for at least 2 h until a buprenorphine-containing adhesivemixture with 6.8% of buprenorphine, with a solids content of 68%(buprenorphine base-containing adhesive mixture) was formed.

Within 24 hours the buprenorphine base-containing adhesive mixture wascoated on a polyethylene terephthalate foil (e.g. Scotchpak from 3M)using a pilot plant roll coater including a drying tunnel, severaldrying sections, an unwinding and laminating station. The solvent wasremoved by drying at approximately 30-50° C. The matrix layer remainedwithin the drying tunnel at approx. 8 minutes. The coating thickness waschosen such that removal of the solvents results in a coating weight ofthe matrix layer of 120 g/m². This results in the 10% by weight ofbuprenorphine base and 7% by weight of levulinic acid and 2.5% by weightof polyvinylpyrrolidone in this matrix layer. The dried film waslaminated with the backing layer (e.g. polyethylenterephthalate (PET)foil 19 μm) to provide the buprenorphine-containing self-adhesive layerstructure.

The individual systems (TTS) were then punched from thebuprenorphine-containing self-adhesive layer structure.

In specific embodiments a TTS as described above can be provided with afurther self-adhesive layer of larger surface area, preferably withrounded corners, comprising a pressure-sensitive adhesive matrix layerwhich is free of active ingredient and has a preferably beige coloredbacking layer (overtape). This is of advantage when the TTS, on thebasis of its physical properties alone, does not adhere sufficiently tothe skin and/or when the buprenorphine-containing matrix layer, for thepurpose of avoiding waste, has pronounced corners (square or rectangularshapes.

The overtape including the TTS are then punched out by only punching theovertape and sealed into pouches of the primary packaging material.

Microscopic pictures were taken of the buprenorphine base-containingadhesive mixture and of the matrix layer using a Nikon S/N 237789Microscope. FIG. 4A shows a microscopic picture of the buprenorphinebase-containing adhesive mixture of Example 4 and FIG. 4B shows amicroscopic picture of the matrix layer of Example 4.

Example 5

The composition of the buprenorphine base-containing adhesive mixtureand the process of manufacture was as described for Example 4. After themixing step forming a buprenorphine containing mixture, thebuprenorphine base-containing adhesive mixture was additionallyhomogenized at a homogenizing speed of 2000 rpm-2500 rpm before coatedon a polyethylene terephthalate film (e.g. Scotchpak from 3M).

In Example 5, films with two different coating weights of the matrixlayer were prepared:

TABLE 5 Coating weight of the Example 5 matrix layer [g/m²] Example 5.1120 Example 5.2 90

Example 6

The composition of the buprenorphine base-containing adhesive mixture issummarized in Table 6 below.

TABLE 6 Ingredient (Trade Name) Amt/unit (kg) Buprenorphine base 1.432Levulinic acid 1.002 Polyvinylpyrrolidone 0.179 Ascorbylacid palmitate0.029 Ethanol 1.014 Polysiloxane adhesive in n-heptane 15.997 Solidscontent of 73% by weight (BIO-PSA 7-4201 from Dow Corning Healthcare)n-heptane 0.346 Total 20

In a 10 l vessel, 1.00 kg of polyvinylpyrrolidone and 3.00 g of ethanolwere dissolved to form a 25% PVP pre-solution. In a homogenizing/mixingvessel: Becomix Lab mixer RW 30 Ex, 0.716 kg of PVP pre-solution, 1.002kg levulinic acid, 0.029 kg of Ascorbyl palmitate and the main part of0.478 kg of Ethanol were suspended by stirring. The prescribed amount ofbuprenorphine was weighed and added to the homogenizing/mixing vesselfollowed by rinsing the weighing container used for buprenorphine withthe remaining part of Ethanol. The mixture was kept under stirring forat least 1 h until a buprenorphine containing solution was formed.15.997 kg of a polysiloxane adhesive in the form of a solution inn-heptane having a solids content of 73% by weight and 0.346 kg ofn-heptane were added to the mixing/homogenizing vessel The mixture wasstirred for at least 2 h until a buprenorphine-containing adhesivemixture with 7.2% of buprenorphine, with a solids content of 72%(buprenorphine base-containing adhesive mixture) was formed.

Within 24 hours the buprenorphine base-containing adhesive mixture wascoated on a polyethylene terephthalate film (e.g. Scotchpak from 3M)using a pilot plant roll coater including a drying tunnel, severaldrying sections, an unwinding and laminating station. The solvent wasremoved by drying at approximately 30-50° C. The matrix layer remainedwithin the drying tunnel at approx. 8 minutes. The coating thickness waschosen such that removal of the solvents results in a specific coatingweight of 120 g/m².

This results in the 10% by weight of buprenorphine base, 7% by weight oflevulinic acid and 1.25% by weight of polyvinylpyrrolidone in thismatrix layer. The dried film was laminated with the backing layer (e.gpolyethylenterephthalate (PET) foil 19 μm) to provide thebuprenorphine-containing self-adhesive layer structure.

The individual systems (TTS) were then punched from thebuprenorphine-containing self-adhesive layer structure. In specificembodiments a TTS as described above can be provided with a furtherself-adhesive layer of larger surface area, preferably with roundedcorners, comprising a pressure-sensitive adhesive matrix layer which isfree of active ingredient and has a preferably skin-colored backinglayer. This is of advantage when the TTS, on the basis of its physicalproperties alone, does not adhere sufficiently to the skin and/or whenthe buprenorphine-containing matrix layer, for the purpose of avoidingwaste, has pronounced corners (square or rectangular shapes).

The overtape including the TTS are then punched out by only punching theovertape and sealed into pouches of the primary packaging material.

Example 7

The composition of the buprenorphine base-containing adhesive mixtureand the process of manufacture was as described for Example 6. After themixing step forming a buprenorphine containing mixture, thebuprenorphine base-containing adhesive mixture was additionallyhomogenized at a homogenizing speed of 2000 rpm-2500 rpm before coatedon a polyethylene terephthalate film (e.g. Scotchpak from 3M).

In Example 7, films with two different coating weights of the matrixlayer were prepared:

TABLE 7 Coating weight of the Example 7 matrix layer [g/m²] Example 7.1120 Example 7.2 90

Example 8

The composition of the buprenorphine base-containing adhesive mixtureand the process of manufacture was as described for Example 6. After themixing step forming a buprenorphine containing mixture, thebuprenorphine base-containing adhesive mixture was additionallyhomogenized at a homogenizing speed of 3500 rpm-4000 rpm before coatedon a polyethylene terephthalate film (e.g. Scotchpak from 3M).

Example 9

In Example 9 the in-vitro dissolution of Comparative Examples 1 and 2,and Examples 3 and 4 were determined using the rotating cylinderapparatus of the Ph Eur/USP. The back of the TTS is affixed to thecylinder element using double sided adhesive tape. Following removal ofthe release liner, the cylinder is lowered into the dissolution medium(600 ml, degassed 0.9% sodium chloride solution at 32° C.) and rotatedat 50 rpm. At 0.5, 2, 8 (or 5) and 24 hours, 4 ml samples are removedand analyzed by a reverse phase HPLC method using a mobile phase of55:45% v/v acetonitrile:0.05 M potassium dihydrogen phosphate (adjustedto pH 3.5) and UV detection at 220 nm. The results are shown in Table 8and FIGS. 5 to 8.

TABLE 8 In vitro dissolution [%] (SD) Elapsed Comparative Comparativetime Example 1 Example 2 Example 3 Example 4 (hr) n = 6 n = 6 n = 6 n =3 0 0 0 0 0 0.5 15 51 8 6 (0.5) (13.3) (0.5) (0) 2 22 59 14 12  (1.0)(13.5) (0.8) (0) 5 29 — 22 — (1.2) (1.1) 8 — — — 24    (2.4) 24 51 95 5244  (1.0) (8.8) (1.6)   (1.3)

Example 10

In Example 10, the in-vitro skin permeation rates of ComparativeExamples 1 and 2 and Norspan® were determined by in vitro experiments inaccordance with the OECD Guideline (adopted Apr. 13, 2004) carried outwith a 9 ml Franz diffusion cell. Split thickness human skin fromcosmetic surgeries (female breast, date of birth 1987) was used. Adermatome was used to prepare skin to a thickness of 800 μm, with anintact epidermis for all examples Comparative Examples 1 and 2 and thecommercial product Norspan®. Diecuts with an area of 1.163 cm² werepunched from Comparative Examples 1 and 2, and were each tested againstdiecuts of the commercial product Norspan®. The concentrations ofbuprenorphine in the receptor medium of the Franz cell (phosphate buffersolution pH 5.5 with 0.1% saline azide as antibacteriological agent) ata temperature of 32±1° C. were measured. The results are shown in Tables9.1 to 9.4 and FIG. 9.

TABLE 9.1 Non-cumulative release [μg/cm²] n = 3 (SD) Elapsed timeComparative Comparative (hr) Example 1 Example 2 Norspan ® 0 0 0 0 81.29 0.48 0.75 (1.71) (0.23) (0.10) 24 19.85 10.75 7.05 (17.70) (2.90)(5.31) 32 16.32 11.27 7.63 (11.50) (2.56) (0.68) 48 35.88 31.67 15.63(18.39) (5.81) (1.70) 72 58.22 69.03 23.73 (17.37) (9.19) (2.05) 144155.33 154.67 56.80 (15.27) (6.41) (3.723) 168 50.88 33.28 18.67 (2.60)(3.47) (1.3)

TABLE 9.2 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) Elapsed time Comparative Comparative (hr) Example 1 Example 2Norspan ® 0 0 0 0 8 0.16 0.06 0.09 (0.21) (0.03) (0.01) 24 1.24 0.670.44 (1.11) (0.18) (0.33) 32 2.04 1.41 0.95 (1.44) (0.32) (0.08) 48 2.241.98 0.98 (1.15) (0.36) (0.11) 72 2.43 2.88 0.99 (0.72) (0.38) (0.09)144 2.16 2.15 0.79 (0.21) (0.09) (0.05) 168 2.12 1.39 0.78 (0.11) (0.14)(0.05)

TABLE 9.3 Cumulative release after 168 hours of release [μg/cm²] n = 3(SD) Comparative Comparative Example 1 Example 2 Norspan ® 337.83 311.17130.33 (82.62) (14.25) (14.05)

TABLE 9.4 Mean cumulative skin permeation rate over 168 hours takinginto account a lag time of 24 hours [μg/cm²-hr] Comparative ComparativeExample 1 Example 2 Norspan ® 2.3 2.2 0.9

Example 11

In Example 11, the in-vitro skin permeation rates of Examples 5 to 8 andBuTrans® were determined by in vitro experiments in accordance with theOECD Guideline (adopted Apr. 13, 2004) carried out with a 9 ml Franzdiffusion cell. Split thickness human skin from cosmetic surgeries(female sample of abdomen region, date of birth 1983) was used. Adermatome was used to prepare skin to a thickness of 800 μm, with anintact epidermis for all examples 5 to 8 and the commercial productBuTrans®. Diecuts with an area of 1.163 cm² were punched from examples 5to 8, and were each tested against diecuts of the commercial productBuTrans®. The concentrations of buprenorphine in the receptor medium ofthe Franz cell (phosphate buffer solution pH 5.5 with 0.1% saline azideas antibacteriological agent) at a temperature of 32±1° C. weremeasured. The results are shown in Tables 10.1 to 10.7 and FIGS. 10 to13.

TABLE 10.1 Non-cumulative release [μg/cm²] n = 3 (SD) Elapsed time (hr)Example 6.1 Example 7.1 Example 8.1 BuTrans ® 0 0 0 0 0 8 1.9 4.4 3.52.1 (0.2) (1.3) (0.6) (0.8) 24 26.0 45.0 33.5 25.2 (3.4) (6.3) (2.1)(6.8) 32 22.9 34.0 27.1 19.4 (3.5) (1.6) (1.3) (3.7) 48 47.8 61.4 51.634.3 (4.6) (1.1) (2.3) (4.2) 72 78.4 88.3 79.6 48.2 (4.6) (2.6) (4.9)(2.8) 144 193.3 203.3 192.3 92.7 (13.1) (9.9) (11.0) (3.3) 168 69.8 75.768.0 28.5 (3.2) (2.4) (1.6) (0.7)

TABLE 10.2 Non-cumulative release [μg/cm²] n = 3 (SD) Elapsed time (hr)Example 7.2 Example 5.2 BuTrans ® 0 0 0 0 8 2.5 2.8 2.1 (0.7) (0.8)(0.8) 24 30.1 35.6 25.2 (4.8) (4.6) (6.8) 32 27.2 30.4 19.4 (3.0) (3.9)(3.7) 48 56.2 62.7 34.3 (3.3) (9.1) (4.2) 72 89.0 96.9 48.2 (0.9) (12.3)(2.8) 144 203.7 216.3 92.7 (12.0) (15.6) (3.3) 168 66.6 70.5 28.5 (8.5)(5.7) (0.7)

TABLE 10.3 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) Elapsed time (hr) Example 6.1 Example 7.1 Example 8.1 BuTrans ® 0 00 0 0 8 0.2 0.5 0.4 0.3 (0.0) (0.2) (0.1) (0.1) 24 1.6 2.8 2.1 1.6 (0.2)(0.4) (0.1) (0.4) 32 2.9 4.2 3.4 2.4 (0.4) (0.2) (0.2) (0.5) 48 3.0 3.83.2 2.1 (0.3) (0.1) (0.1) (0.3) 72 3.3 3.7 3.3 2.0 (0.3) (0.1) (0.2)(0.1) 144 2.7 2.8 2.7 1.3 (0.2) (0.1) (0.2) (0.0) 168 2.9 3.2 2.8 1.2(0.1) (0.1) (0.1) (0.0)

TABLE 10.4 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) Elapsed time (hr) Example 7.2 Example 5.2 BuTrans ® 0 0 0 0 8 0.30.4 0.3 (0.1) (0.1) (0.1) 24 1.9 2.2 1.6 (0.3) (0.3) (0.4) 32 3.4 3.82.4 (0.4) (0.5) (0.5) 48 3.5 3.9 2.1 (0.2) (0.6) (0.3) 72 3.7 4.0 2.0(0.0) (0.5) (0.1) 144 2.8 3.0 1.3 (0.2) (0.2) (0.0) 168 2.8 2.9 1.2(0.4) (0.2) (0.0)

TABLE 10.5 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) and per area of release [μg/hr] BuTrans ® Elapsed Sample Area ofArea of time interval release release (hr) (hr) (cm²) Example 5.2 (25cm²) 0 0 0 0 8 8 0.4 0.3 (0.1) (0.1) 10 3.5 6.7 14 4.9 6.7 24 16 2.2 1.6(0.3) (0.4) 10 22.2 39.4 14 31.1 39.4 32 8 3.8 2.4 (0.5) (0.5) 10 38.060.7 14 53.1 60.7 48 16 3.9 2.1 (0.6) (0.3) 10 39.2 53.6 14 54.8 53.6 7224 4.0 2.0 (0.5) (0.1) 10 40.4 50.2 14 56.5 50.2 144 72 3.0 1.3 (0.2)(0.0) 10 30.0 32.2 14 42.1 32.2 168 24 2.9 1.2 (0.2) (0.0) 10 29.4 29.714 41.1 29.7

TABLE 10.6 Cumulative release after 168 hours of release [μg/cm²] n = 3(SD) Example 5.2 BuTrans ® 515.3 250.7 (44.1) (17.1)

TABLE 10.7 Mean cumulative skin permeation rate over 168 hours takinginto account a lag time of 24 hours [μg/cm²-hr] Example 5.2 BuTrans ®3.6 1.7

1.-63. (canceled)
 64. A transdermal therapeutic system for transdermaladministration of buprenorphine, comprising a buprenorphine-containingself-adhesive layer structure comprising A) a buprenorphine-impermeablebacking layer, and B) a buprenorphine-containing pressure-sensitiveadhesive layer on said buprenorphine-impermeable backing layer, saidadhesive layer comprising a) at least one polymer-basedpressure-sensitive adhesive, b) an analgesically effective amount ofbuprenorphine base or a pharmaceutically acceptable salt thereof, c) aviscosity-increasing substance in an amount of about 0.1% to about 8% ofsaid buprenorphine-containing pressure-sensitive adhesive layer, and d)a carboxylic acid selected from the group consisting of oleic acid,linoleic acid, linolenic acid, levulinic acid and mixtures thereof, inan amount sufficient so that said analgesically effective amount ofbuprenorphine is solubilized therein to form a mixture including saidviscosity-increasing substance, and wherein said carboxylic acid-,buprenorphine- and viscosity-increasing substance-containing mixtureforms dispersed deposits in said pressure-sensitive adhesive, andwherein said buprenorphine-containing pressure-sensitive adhesive layeris the skin contact layer.
 65. A transdermal therapeutic system fortransdermal administration of buprenorphine, comprising abuprenorphine-containing self-adhesive layer structure comprising A) abuprenorphine-impermeable backing layer, and B) abuprenorphine-containing pressure-sensitive adhesive layer on saidbuprenorphine-impermeable backing layer, said adhesive layer comprisinga) at least one polymer-based pressure-sensitive adhesive, b) ananalgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, c) solublepolyvinylpyrrolidone, and d) a carboxylic acid selected from the groupconsisting of oleic acid, linoleic acid, linolenic acid, levulinic acidand mixtures thereof, in an amount sufficient so that said analgesicallyeffective amount of buprenorphine is solubilized therein to form amixture including said polyvinylpyrrolidone, and wherein said carboxylicacid-, buprenorphine- and polyvinylpyrrolidone-containing mixture formsdispersed deposits in said pressure-sensitive adhesive, and wherein saidbuprenorphine-containing pressure-sensitive adhesive layer is the skincontact layer.
 66. The transdermal therapeutic system of claim 65,wherein said polyvinylpyrrolidone has a K-Value of at least about 5, orof at least about 10, or of at least about 15, or of at least about 20,or of at least about 50, or of at least about
 80. 67. The transdermaltherapeutic system of claim 64, wherein said buprenorphine is present inthe form of buprenorphine base and/or wherein said carboxylic acid islevulinic acid.
 68. The transdermal therapeutic system of claim 64,wherein said polymer-based pressure-sensitive adhesive is based onpolysiloxanes or polyisobutylenes.
 69. The transdermal therapeuticsystem of claim 64, wherein said buprenorphine is present in the form ofbuprenorphine base, said carboxylic acid is levulinic acid and saidpolymer-based pressure-sensitive adhesive is based on polysiloxanes. 70.The transdermal therapeutic system of claim 64, wherein saidviscosity-increasing substance is present in an amount of about 0.1% toabout 7%, or of about 0.5% to about 5%, or of about 1% to about 4%, orof about 2% to about 3% of said buprenorphine-containingpressure-sensitive adhesive layer.
 71. The transdermal therapeuticsystem of claim 64, wherein said viscosity-increasing substancecomprises one or more cellulose derivatives selected from the groupconsisting of methylcellulose, ethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, sodium carboxymethylcellulose ormicrocrystalline cellulose.
 72. The transdermal therapeutic system ofclaim 64, wherein said viscosity-increasing substance comprises one ormore high molecular mass polyacrylic acids, salts thereof or derivativesthereof.
 73. The transdermal therapeutic system of claim 64, whereinsaid viscosity-increasing substance comprises one or more ofpolyvinylpyrrolidone, colloidal silicone dioxide, sodium alginate,tragacanth, xanthan gum, bentonite, carageenan or guar gum.
 74. Thetransdermal therapeutic system of claim 64, wherein said buprenorphineis present in the form of buprenorphine base, said carboxylic acid islevulinic acid, said polymer-based pressure-sensitive adhesive is basedon polysiloxanes and said viscosity-increasing substance is solublepolyvinylpyrrolidone in an amount of about 1% to about 4%.
 75. Thetransdermal therapeutic system of claim 64, wherein said amount of saidbuprenorphine contained in the transdermal therapeutic system rangesfrom about 1 mg to about 4 mg buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof, or about 3.5 mg to about8 mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, or about 6.5 mg to about 16 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof, or about 11.5 mg to about 24 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof, or about15 mg to about 32 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof.
 76. The transdermaltherapeutic system of claim 64, wherein said buprenorphine-containingpressure-sensitive adhesive layer has a size that provides an area ofrelease ranging from about 1 cm² to about 4.8 cm², or about 3 cm² toabout 9.5 cm², or about 6 cm² to about 19 cm², or about 12 cm² to about28.5 cm², or about 16 cm² to about 38 cm².
 77. The transdermaltherapeutic system of claim 64, wherein said buprenorphine-containingpressure-sensitive adhesive layer has a size that provides an area ofrelease ranging from about 1 cm² to about 4.8 cm² and said amount ofsaid buprenorphine contained in the transdermal therapeutic systemranges from about 1 mg to about 4 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof, wherein saidtransdermal therapeutic system provides a nominal mean release rate ofabout 5 μg/hr over about 168 hours of administration.
 78. Thetransdermal therapeutic system of claim 64, wherein saidbuprenorphine-containing pressure-sensitive adhesive layer has a sizethat provides an area of release ranging from about 3 cm² to about 9.5cm², and said amount of said buprenorphine contained in the transdermaltherapeutic system ranges from about 3.5 mg to about 8 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof, wherein said transdermal therapeutic system provides a nominalmean release rate of about 10 μg/hr over about 168 hours ofadministration.
 79. The transdermal therapeutic system of claim 64,wherein said buprenorphine-containing pressure-sensitive adhesive layerhas a size that provides an area of release ranging from about 6 cm² toabout 19 cm² and said amount of said buprenorphine contained in thetransdermal therapeutic system ranges from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, wherein said transdermal therapeutic systemprovides a nominal mean release rate of about 20 μg/hr over about 168hours of administration.
 80. The transdermal therapeutic system of claim64, wherein said buprenorphine-containing pressure-sensitive adhesivelayer has a size that provides an area of release ranging from about 12cm² to about 28.5 cm², and said amount of said buprenorphine containedin the transdermal therapeutic system ranges from about 11.5 mg to about24 mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, wherein said transdermal therapeutic systemprovides a nominal mean release rate of about 30 μg/hr over about 168hours of administration.
 81. The transdermal therapeutic system of claim64, wherein said buprenorphine-containing pressure-sensitive adhesivelayer has a size that provides an area of release ranging from about 16cm² to about 38 cm², and said amount of said buprenorphine contained inthe transdermal therapeutic system ranges from about 15 mg to about 32mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, wherein said transdermal therapeutic systemprovides a nominal mean release rate of about 40 μg/hr over about 168hours of administration.
 82. The transdermal therapeutic system of claim64, wherein said buprenorphine is present in the form of buprenorphinebase and said system provides a mean cumulative skin permeation ratemeasured in a Franz diffusion cell with dermatomed human skin of morethan 1.3 μg/cm²-hr over a 168 hours test and/or provides a cumulativerelease of buprenorphine base as measured in a Franz diffusion cell withdermatomed human skin of 220 μg/cm² to 640 μg/cm² over a time period of168 hours.
 83. The transdermal therapeutic system of claim 64, whereinsaid buprenorphine is present in the form of buprenorphine base and saidsystem provides a non-cumulative release of buprenorphine base asmeasured in a Franz diffusion cell with dermatomed human skin of 2μg/cm² to 10 μg/cm² in the first 8 hours, 20 μg/cm² to 80 μg/cm² fromhour 8 to hour 24, 20 μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30μg/cm² to 120 μg/cm² from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm²from hour 48 to hour 72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour144, and 30 μg/cm² to 100 μg/cm² from hour 144 to hour
 168. 84. Thetransdermal therapeutic system of claim 65, wherein said buprenorphineis present in the form of buprenorphine base and said system provides anon-cumulative release of buprenorphine base as measured in a Franzdiffusion cell with dermatomed human skin of 2 μg/cm² to 10 μg/cm² inthe first 8 hours, 20 μg/cm² to 80 μg/cm² from hour 8 to hour 24, 20μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30 μg/cm² to 120 μg/cm²from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm² from hour 48 to hour72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and 30 μg/cm² to100 μg/cm² from hour 144 to hour
 168. 85. A set of two to five differenttransdermal therapeutic systems each in accordance with claim 64,wherein said first transdermal therapeutic system provides a size ofsaid buprenorphine-containing pressure-sensitive adhesive layerproviding an area of release ranging from about 1 cm² to about 4.8 cm²and contains an amount of said buprenorphine from about 1 mg to about 4mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; said second transdermal therapeutic systemprovides a size of said buprenorphine-containing pressure-sensitiveadhesive layer providing an area of release ranging from about 3 cm² toabout 9.5 cm² and contains an amount of said buprenorphine from about3.5 mg to about 8 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof; said third transdermaltherapeutic system provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing an area of release rangingfrom about 6 cm² to about 19 cm² and contains an amount of saidbuprenorphine from about 6.5 mg to about 16 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof; saidfourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing anarea of release ranging from about 12 cm² to about 28.5 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; and said fifth transdermal therapeutic systemprovides a size of said buprenorphine-containing pressure-sensitiveadhesive layer providing an area of release ranging from about 16 cm² toabout 38 cm² and contains an amount of said buprenorphine from about 15mg to about 32 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof.
 86. The transdermaltherapeutic system of claim 64, wherein said buprenorphinebase-containing pressure-sensitive adhesive layer comprises ananti-oxidant selected from the group consisting of ascorbyl palmitate,tocopherol and esters thereof, ascorbic acid, butylhydroxytoluene,butylhydroxyanisole, propyl gallate and mixtures thereof.
 87. Thetransdermal therapeutic system of claim 86, wherein said anti-oxidant isascorbyl palmitate and is present in an amount of from about 0.01 toabout 0.5% of said buprenorphine-containing pressure-sensitive adhesivelayer.
 88. A method of treating pain in a patient comprising applying atransdermal therapeutic system for transdermal administration ofbuprenorphine to the skin of said patient, wherein said transdermaltherapeutic system comprises a buprenorphine-containing self-adhesivelayer structure comprising A) a buprenorphine-impermeable backing layer,and B) a buprenorphine-containing pressure-sensitive adhesive layer onsaid buprenorphine-impermeable backing layer, said adhesive layercomprising a) at least one polymer-based pressure-sensitive adhesive, b)an analgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, c) a viscosity-increasingsubstance in an amount of about 0.1% to about 8% of saidbuprenorphine-containing pressure-sensitive adhesive layer, and d) acarboxylic acid selected from the group consisting of oleic acid,linoleic acid, linolenic acid, levulinic acid and mixtures thereof, inan amount sufficient so that said analgesically effective amount ofbuprenorphine is solubilized therein to form a mixture including saidviscosity-increasing substance, and wherein said carboxylic acid-,buprenorphine- and viscosity-increasing substance-containing mixtureforms dispersed deposits in said pressure-sensitive adhesive, andwherein said buprenorphine-containing pressure-sensitive adhesive layeris the skin contact layer.
 89. The method claim 88, wherein saidtransdermal therapeutic system is applied on the skin of the patient formore than 96 hours.
 90. The method claim 88, wherein said transdermaltherapeutic system is applied on the skin of the patient for about 168hours.
 91. A method of manufacturing said transdermal therapeutic systemof claim 64, comprising the steps of
 1. providing abuprenorphine-containing adhesive mixture comprising a) buprenorphinebase or a pharmaceutically acceptable salt thereof, b) a carboxylicacid, c) a viscosity-increasing substance, d) a polymer-basedpressure-sensitive adhesive, and e) a solvent;
 2. storing said mixturebetween 0 hours and 6 days;
 3. homogenizing saidbuprenorphine-containing adhesive mixture;
 4. storing said homogenizedmixture between 0 hours and 6 days;
 5. coating saidbuprenorphine-containing adhesive mixture on a film using a rollercoater in an amount to provide the desired coating dry weight;
 6. dryingsaid coated buprenorphine-containing adhesive mixture to provide abuprenorphine-containing adhesive layer with the desired coating dryweight;
 7. optionally laminating said buprenorphine-containing adhesivelayer to a backing layer to provide a buprenorphine-containing adhesivelayer structure;
 8. optionally punching individual systems from thebuprenorphine-containing self-adhesive layer structure with the desiredarea of release; and
 9. optionally adhering to the individual systems anactive-free self-adhesive layer structure comprising a backing layer andan active agent-free pressure-sensitive adhesive layer and which islarger than the individual systems of buprenorphine-containingself-adhesive layer structure.
 92. The method of claim 91, wherein saidviscosity-increasing substance is polyvinylpyrrolidone, and wherein saidpolyvinylpyrrolidone is used to control said deposit size during themanufacture.
 93. The method of claim 91, wherein in step 1 saidbuprenorphine is present in the form of buprenorphine base, saidcarboxylic acid is levulinic acid and said viscosity-increasingsubstance is polyvinylpyrrolidone, and are dissolved in ethanol andsubsequently suspended in a polymer-based pressure-sensitive adhesivebased on polysiloxane in heptane to provide the buprenorphine-containingadhesive mixture.